Lysophosphatidic acid receptor 1 (lpar1) inhibitor compounds

ABSTRACT

The present invention provides a compound of formula (I) or a pharmaceutical salt thereof, use, methods for its preparation are described.

This invention provides lysophosphatidic acid receptor 1 (LPAR1)inhibitor compounds and pharmaceutically acceptable salts thereof, andtheir use in therapy.

LPAR1 is the first high-affinity receptor identified forlysophosphatidic acids (LPA), which are small bioactiveglycerophospholipids. LPA-mediated LPAR1 activation implicates numerouscellular responses including cell proliferation, migration, andsurvival. Particularly, the LPA-LPAR1 pathway may contribute to thedevelopment of non-alcoholic steatohepatitis (NASH), which is a liverdisease characterized by fat deposits, inflammation and tissue damage.NASH progression leads to the accumulation of scarring, or fibrosis, inthe liver. If further advanced, NASH can cause cirrhosis and portalhypertension. About 2-5 percent of adult Americans and up to 20 percentof those who are obese may suffer from NASH. Beyond fibrosis andcirrhosis, NASH may progress to hepatocellular carcinoma and liverfailure.

It has been suggested that inhibition of LPAR1 may be useful in treatinginflammation, fibrosis, and other LPAR1-mediated diseases or disorders.For example, U.S. Pat. No. 9,272,990 discloses LPAR antagonists fortreating fibrosis.

PCT Publication No. WO 2017/086430 discloses an a halogen-substitutedthiophene compound as LPAR1 antagonist for the treatment and/orprophylaxis of NASH.

There is an unmet need for LPAR1 antagonist compounds that may be usefulfor treating NASH as well as other LPAR1-mediated diseases or disorders.Thus, the present invention provides compounds which display potent andselective LPAR1 antagonist activities in vitro, as well as efficacy inan animal model of liver inflammation and fibrosis. Further, the presentinvention provides ester prodrug of such LPAR1 antagonist compounds.Particularly, the present invention provides a compound of Formula I

wherein,

-   -   X¹ and X² are each independently CH or N, and X³ is C—R² or N,        provided that when X¹ is CH, then X² is CH and X³ is C—R², and        provided that when X¹ is N, then no more than one of X² and X³        may be N;    -   Y¹ and Y² are CH or N, provided that only one of Y¹ or Y² may be        N;    -   R¹ is        -   isopropyl,        -   isobutyl,        -   t-butyl,        -   2-hydroxyprop-2-yl,        -   cyclopropyl,        -   cyclopropyloxy,        -   t-butyloxy,        -   cyclobutyloxy,        -   3,3-difluorocyclobutyloxy,        -   2-fluoroprop-2-yl,        -   1,1-difluoroethyl,        -   trifluoromethyl,        -   isopropyloxy, or        -   2-methoxyprop-2-yl;    -   R² is H or fluoro;    -   R³ is H, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkoxymethyl,        CF₃, cyanomethyl or cyano;    -   R⁴ is H, halogen, C₁-C₃ alkyl, CF₃ or cyano;    -   R⁵ is H, methyl, ethyl, propyl, isopropyl, or cyclopropyl; or        a pharmaceutically acceptable salt thereof.

In one embodiment, X¹ is N.

In one embodiment, X¹ is CH.

In one embodiment, Y¹ is CH.

In one embodiment, R¹ is isopropyl.

In one embodiment, R¹ is cyclopropyloxy.

In one embodiment, R³ is H, methyl, methoxymethyl, cyanomethyl or cyano.

In one embodiment, R⁴ is H, methyl, CF₃, or cyano.

In one embodiment, R⁵ is H.

In another embodiment, a compound of the present invention is any one ofthe compounds of the examples, or a pharmaceutically acceptable saltthereof.

In another aspect of the present invention there is provided apharmaceutical composition, comprising a compound of Formula I, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier, diluent, or excipient. This aspectof the invention also provides a pharmaceutical composition for treatingNASH in a mammal, particularly a human, comprising a compound of FormulaI, or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients, carriers, or diluents.Furthermore, this aspect of the present invention provides apharmaceutical composition for treating fibrosis in a mammal,particularly a human, as for example pulmonary fibrosis, liver fibrosis,kidney fibrosis, heart fibrosis or skin fibrosis, comprising a compoundof Formula I, or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable excipients, carriers, or diluents.Furthermore, this aspect of the present invention provides apharmaceutical composition for treating inflammatory diseases in amammal, particularly a human, as for example chronic respiratorydisease, chronic obstructive pulmonary disease (COPD), multiplesclerosis, rheumatoid arthritis, osteoarthritis, psoriasis, systemiclupus erythematosus, scleroderma, Sjorgen's syndrome, ulcerative colitisand Crohn's disease, comprising a compound of Formula I, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients, carriers, or diluents.

In another aspect of the present invention there is provided a method oftreating NASH in a mammal, particularly a human, comprisingadministering to a mammal in need of such treatment an effective amountof a compound of Formula I, or a pharmaceutically acceptable saltthereof.

In one embodiment of this aspect of the present invention provides amethod of treating fibrosis in a mammal, particularly a human, as forexample pulmonary fibrosis, liver fibrosis, kidney fibrosis, heartfibrosis or skin fibrosis, comprising administering to a mammal in needof such treatment an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In another embodiment of this aspect of the present invention provides amethod of treating treating inflammatory diseases in a mammal,particularly a human, as for example chronic respiratory disease,chronic obstructive pulmonary disease (COPD), multiple sclerosis,rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupuserythematosus, scleroderma, Sjorgen's syndrome, ulcerative colitis andCrohn's disease, comprising administering to a mammal in need of suchtreatment an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In another aspect of the present invention there is provided a compoundof Formula I, or a pharmaceutically acceptable salt thereof for use intherapy. Within this aspect, the invention provides a compound ofFormula I, or a pharmaceutically acceptable salt thereof, for use in thetreatment of NASH in a mammal, particularly a human. The presentinvention also provides a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of fibrosis in amammal, particularly a human, as for example pulmonary fibrosis, liverfibrosis, kidney fibrosis, heart fibrosis or skin fibrosis. The presentinvention also provides a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of inflammatorydiseases in a mammal, particularly a human. In an embodiment of thisaspect of the invention said inflammatory disease is selected from thegroup consisting of, but not limited to, chronic respiratory disease,chronic obstructive pulmonary disease (COPD), multiple sclerosis,rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupuserythematosus, scleroderma, Sjorgen's syndrome, ulcerative colitis andCrohn's disease

Another aspect of the present invention provides the use of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of NASH in a mammal.

Another aspect of the present invention provides the use of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of fibrosis in a mammal.

A further aspect of the present invention provides the use of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of inflammatory diseasesin a mammal. In an embodiment of this aspect of the invention saidinflammatory disease is selected from the group consisting of, but notlimited to, chronic respiratory disease, chronic obstructive pulmonarydisease (COPD), multiple sclerosis, rheumatoid arthritis,osteoarthritis, psoriasis, systemic lupus erythematosus, scleroderma,Sjorgen's syndrome, ulcerative colitis and Crohn's disease.

As used herein, the term “effective amount” or “therapeuticallyeffective amount” of a compound refers to an amount, or a dosage, whichis effective in treating a disorder or a disease, such as NASH,fibrosis, inflammatory diseases, other LPAR1-mediated diseases ordisorders as described herein. The attending diagnostician, as oneskilled in the art, can readily determine an effective amount by the useof conventional techniques and by observing results obtained underanalogous circumstances. In determining the effective amount or dose ofa compound, a number of factors are considered, including but notlimited to, the compound to be administered; the co-administration ofother agents, if used; the species of mammal; its size, age, and generalhealth; the degree of involvement or the severity of the disorder; theresponse of the individual patient; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; the use of other concomitant medication; andother relevant circumstances.

The terms “treatment” and “treating” as used herein are intended torefer to all processes wherein there may be a slowing, interrupting,arresting, controlling, or stopping of the progression of an existingdisorder and/or symptoms thereof, but does not necessarily indicate atotal elimination of all symptoms.

The term “pharmaceutically acceptable carrier, diluent, or excipients”means that the carrier, diluent, and excipients are pharmaceuticallycompatible with the other ingredients of the composition. In aparticular embodiment, the pharmaceutical compositions are formulated asa tablet or capsule for oral administration. The tablet or capsule caninclude a compound of the present invention in an amount effective totreat fibrosis, inflammatory diseases, NASH, other LPAR1-mediateddiseases or disorders.

As used herein, the term “fibrosis” refers to the formation or presenceof excessive connective tissue in an organ or tissue. Fibrosis may occuras a repair or replacement response to a stimulus such as tissue injuryor inflammation. A hallmark of fibrosis is the production of excessiveextracellular matrix. The normal physiological response to injuryresults in the deposition of connective tissue as part of the healingprocess, but this connective tissue deposition may persist and becomepathological, altering the architecture and function of the tissue. Inexemplary embodiments, the fibrosis is pulmonary fibrosis, liverfibrosis, kidney fibrosis, heart fibrosis, or skin fibrosis.

While it is possible to administer compounds employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising the compound of Formula I, or a pharmaceutically acceptablesalt thereof, as an active ingredient and at least one pharmaceuticallyacceptable carrier, diluent and/or excipient. These compositions can beadministered by a variety of routes including oral, sublingual, nasal,subcutaneous, intravenous, and intramuscular. Such pharmaceuticalcompositions and processes for preparing them are well known in the art.See, e.g., Remington: The Science and Practice of Pharmacy (Universityof the Sciences in Philadelphia, ed., 21^(st) ed., Lippincott Williams &Wilkins Co., 2005).

Compounds of Formula I are generally effective over a wide dosage range.For example, dosages per day normally fall within the range of about 0.2mg/kg to about 15 mg/kg, more usually from about 0.7 mg/kg to about 7.5mg/kg, and as for example about 1.5 mg/kg of body weight. In someinstances dosage levels below the lower limit of the aforesaid range maybe more than adequate, while in other cases still larger doses may beemployed without causing any harmful side effect, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. It may also be advantageous to administer the daily dose inparts over the course of each day (e.g. 1/2 dose twice a day or 1/3 dosethree times a day). It will be understood that the amount of thecompound actually administered will be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compound orcompounds administered, the age, weight, and response of the individualpatient, and the severity of the patient's symptoms.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 20 to about 2000 mg, more usually about 50to about 500 mg, as for example about 200 mg of the active ingredient.The term “unit dosage form” refers to physically discrete units suitableas unitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with at least onesuitable pharmaceutically acceptable carrier, diluent and/or excipient.

Compounds of this invention have basic and acidic moieties, andaccordingly react with a number of organic and inorganic acids and basesto form pharmaceutically acceptable salts. Pharmaceutically acceptablesalts of the compound of the present invention are contemplated withinthe scope of the present application. The term “pharmaceuticallyacceptable salt” as used herein, refers to any salt of the compound ofthe invention that is substantially non-toxic to living organisms. Suchpharmaceutically acceptable salts and common methodology for preparingthem are well known in the art. See, e.g., P. Stahl, et al., HANDBOOK OFPHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH,2008); and S. M. Berge, et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Sciences, Vol 66, No. 1, January 1977.

Abbreviations used herein are defined as follows:

“Brine” means saturated NaCl.

“BSA” means bovine serum albumin

“DAST” means diethylaminosulfur trifluoride

“DCM” means dichloromethane.

“DMF” means n,n-dimethylformamide

“DMSO” means dimethyl sulfoxide (perdeuterated [d6] if for NMR).

“EtOAc” means ethyl acetate.

“FLIPR” means fluorescence imaging plate reader.

“HBSS” means Hank's Buffered Salt Solution.

“HEPES” means 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid.

“HPLC” means high pressure liquid chromatography.

“hr.” or “h” means hour or hours.

“IC₅₀” means the concentration at which 50% of the maximum inhibition isachieved.

“LCMS” means liquid chromatography mass spectrometry.

“MeOH” means methanol.

“MS” means mass spectroscopy or mass spectrum.

“MTBE” means methyl tert-butyl ether.

“PE” means petroleum ether solvent.

“THF” means tetrahydrofuran.

A compound of Formula I may be prepared by processes known in thechemical arts or by a novel process described herein. A process for thepreparation of a compound of Formula I and novel intermediates for themanufacture of a compound of Formula I, provide further features of theinvention and are illustrated by the following procedures.

Generally, a compound of Formula I may be prepared from a compound ofFormula II (Scheme 1). More specifically, a compound of Formula II isreacted with a compound of Formula III in the presence of a suitabletransition metal catalysis such as tris(dibenylideneacetone)dipalladiumand a base such as cesium carbonate in a suitable solvent to provide acompound of Formula I. Suitable solvents include dioxane. A compound ofFormula III may be prepared by methods known in the chemical arts aswell as methods provided in the Preparations and Examples.

Alternatively, a compound of Formula I may be prepared from a compoundof Formula IV (Scheme 1). More specifically, a compound of Formula IV isreacted with a suitable R¹-boron reagent compound in the presence of asuitable transition metal catalysis such astris(dibenylideneacetone)dipalladium and a base such as cesium carbonatein a suitable solvent to provide a compound of Formula I. Suitablesolvents include dioxane. A suitable R¹-boron reagent compound may beprepared by methods known in the chemical arts as well as methodsprovided in the Preparations and Examples.

It is understood that certain functional groups employed during thepreparation of a compound of Formula I may act as precursors to groupsultimately encompassed in a compound of Formula I. Such groups are knownin the chemical arts and may be disclosed in the Preparations andExamples. For instance, the R5-O—(C═O)— group of a compound of Formula Imay be acquired through chemical transformation a suitable precursorgroup such as cyano (—CN).

Alternatively, a compound of Formula I may be prepared from a compoundof Formula V and a compound of Formula VI (Scheme 2). More specifically,a compound of Formula VI is first reacted with bis(pinacolato)diboron inthe presence of a suitable transition metal catalyst such as[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium in a suitablesolvent such as dioxane to provide an intermediate pinacolatoboroncompound which is further reacted compound of Formula V in the presenceof a base such as sodium carbonate to provide a compound of Formula I. Acompound of Formula V or a compound of Formula VI may be prepared bymethods known in the chemical arts as well as methods provided in thePreparations and Examples.

As shown in Scheme 3, compounds of Formula II may be prepared byreacting a compound of Formula VIII with a pinacolatoboron compound ofFormula VII in the presence of a suitable transition metal catalysissuch as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and asuitable base such as sodium carbonate in a suitable solvent. Suitablesolvents include dioxane.

It is understood reacting groups suitable for coupling methods are knownin the chemical arts as well as disclosed in the Preparations andExamples. For instance, the pinacolatoboron reacting group of a compoundof Formula VII may be substituted with alternative coupling groups suchas tributylstannyl.

Alternatively, a compound of Formula II may be prepared from a compoundof Formula IX (Scheme 3). More specifically, a compound of Formula IX isreacted with 4-bromo-2-methyl-pyrazol-3-amine in the presence of asuitable transition metal catalysis such astris(dibenylideneacetone)dipalladium and a base such as cesium carbonatein a suitable solvent to provide a compound of Formula II. Suitablesolvents include dioxane.

A compound of Formula VII, Formula VIII or Formula IX may be prepared bymethods known in the chemical arts as well as methods provided in thePreparations and Examples.

PREPARATION 1 2-chloro-6-(cyclopropoxy)pyrazine

Add sodium hydride (1.36 g, 34.1 mmol, 60 mass %) to cyclopropanol (1.00g, 17.0 mmol) in tetrahydrofuran (10 mL) at 0° C., and the reactionmixture is stirred at 20° C. for 30 min. Then 2, 6-dichloropyrazine(2.57 g, 17.0 mmol) is added and the mixture is stirred at 20° C. for 12h. The reaction mixture is poured into saturated NH₄Cl (30 mL). Theresulting mixture is extracted with EtOAc (30 mL×3). The combinedorganic phases are washed with water (30 mL), brine (30 mL), dried overanhydrous sodium sulfate, filtered and concentrated to afford titlecompound (2.50 g, 81.7%) as a white solid. LCMS (m/z): 170.9 [M+H]⁺.

PREPARATION 2 2-chloro-6-(1, 1-difluoroethyl)pyrazine

1. Synthesis of 1-(6-chloropyrazin-2-yl)ethanone

Add 2, 6-dichloropyrazine (3.00 g, 20.1 mmol) andtetrakis(triphenylphosphine) palladium (2.33 g, 2.01 mmol) totributyl(1-ethoxyvinyl)stannane (8.08 g, 22.2 mmol) in anhydrous toluene(100 mL) under N₂ atmosphere. Then the mixture is stirred at 100° C.under N₂ atmosphere for 16 hrs. After cooling to room temperature, themixture is poured into a mixture of sat. KF aq. (300 mL) and MTBE/EtOAc(1/1, 200 mL) and stirred for 1 h. The solids are filtered on celite andwashed with MTBE/EtOAc (1/1, 150 mL×2). The filtrate is separated. Theaqueous layer is extracted with EtOAc (200 mL). The combined organiclayer is concentrated under reduced pressure. The residue is taken up inacetone (200 mL) and treated with 1 N HCl aq. (120 mL), stirred at10-15° C. for 1 h. The mixture is concentrated under reduced pressure toremove most acetone, and the residue is extracted with MTBE/EtOAc (1/1,100 mL×3). The combined organic layer is washed with sat. NaHCO₃ (150mL×2), brine (150 mL×2), dried over anhydrous Na₂SO₄, filtered,concentrated under reduced pressure, the residue is purified by columnchromatography on silica gel eluting with 0-10% EtOAc in PE to affordtitle compound (1.0 g, 31.4%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=9.14 (s, 1H), 8.80 (s, 1H), 2.74 (s, 3H).

2. Synthesis of 2-chloro-6-(1,1-difluoroethyl)pyrazine

Add diethylaminosulfur trifluoride (2.81 g, 17.2 mmol) to1-(6-chloropyrazin-2-yl)ethanone (540 mg, 1.15 mmol) in dichloromethane(30 mL) at 0° C. and the solution is stirred at 15° C. for 12 h. Thereaction mixture is poured into ice water (30 mL), and aq. Na₂CO₃ (10%mass in water) is added dropwise to adjust pH=8. The reaction mixture isdiluted with 30 mL water and extracted with DCM (40 mL×3). The organiclayer is dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford crude product (800 mg) as yellow oil. The crudeproduct is purified by column chromatography on silica gel eluting with0-30% EA in PE to give title compound (385 mg, 90 mass %, 56.3%) as ayellow oil.

¹H NMR (400 MHz, CDCl₃): δ=8.86 (s, 1H), 8.71 (s, 1H), 2.05 (t, J=18.4Hz, 3H).

PREPARATION 3 2-chloro-6-(1-fluoro-1-methyl-ethyl)pyrazine

1. Synthesis of 2-(6-chloropyrazin-2-yl)propan-2-ol

Add methyl 6-chloropyrazine-2-carboxylate (20.0 g, 116 mmol) in THF (100mL) to methylmagnesium bromide (3.0 mol/L) in diethyl ether (120 g, 348mmol, 3.0 mol/L) at 0° C. and the mixture is stirred at this temperaturefor 2 h. The reaction is quenched with 1.0 M HCl solution (100 mL) andextracted with EtOAc (100 mL×3). The combined organic layers are washedwith brine (100 mL), dried over anhydrous sodium sulfate, concentratedto afford a yellow oil. The yellow oil is purified by columnchromatography on silica gel eluting with 0-30% EA in PE to afford titlecompound (3.80 g, 18.0%) as brown oil. LCMS (m/z): 172.8 [M+H]⁺.

2. Synthesis of 2-chloro-6-(1-fluoro-1-methyl-ethyl)pyrazine

Add DAST (6.74 g, 41.8 mmol) to 2-(6-chloropyrazin-2-yl)propan-2-ol(3.80 g, 20.9 mmol) in CH₂Cl₂ (30 mL) at 0° C., then the reactionmixture is stirred at 0° C. for 1 h. The reaction is quenched with water(20 mL) and extracted with EtOAc (50 mL×3). The combined organic layersare washed with sat. NaHCO₃ (20 mL), 1 M HCl (20 mL) and brine (30 mL),and dried over anhydrous sodium sulfate and to afford a yellow oil. Thecrude product was purified column chromatography on silica gel elutingwith 0-30% EA in PE to afford title compound (3.40 g, 84%) as yellowoil. LCMS (m/z): 174.9 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ=8.75 (s, 1H), 8.53 (s, 1H), 1.76 (d, J=22.4Hz, 6H)

PREPARATION 4 2-chloro-6-isopropoxy-pyrazine

Add sodium hydride in oil (1.07 g, 26.8 mmol, 60 mass %) to propan-2-ol(0.807 g, 13.4 mmol) in THF (20 mL) at 0° C. and the mixture is stirredfor 20 min at this temperature. Then 2,6-dichloropyrazine (2.00 g, 13.4mmol) is added and the mixture is stirred at 20° C. for 18 hours. Thereaction mixture is poured into a saturated NH₄Cl solution (100 mL) andextracted with EtOAc (50 mL×2). The combined organic layers are washedwith brine, dried over sodium sulfate and concentrated to afford thetitle compound (2.20 g, 85.4%) as brown oil.

¹H NMR (400 MHz, CDCl₃) δ=7.93 (s, 1H), 7.88 (s, 1H), 5.25-5.04 (m, 1H),1.21 (d, J=6.4 Hz, 6H).

PREPARATION 5 2-chloro-6-isopropyl-pyrazine

1. Synthesis of 2-chloro-6-isopropenyl-pyrazine

Add 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.00 g, 35.4mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)(1.32 g, 1.77 mmol) and sodium carbonate (9.37 g, 88.4 mmol) to2,6-dichloropyrazine (10.6 g, 70.7 mmol) in 1,4-dioxane (80 mL) andwater (20 mL) to under N₂. The mixture is stirred at 100° C. for 6hours. The solid is filtered off. The mixture is diluted with water (100mL) and extracted with EtOAc (200 mL×3). The combined organic layers arewashed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered andevaporated to afford the crude product. The crude product is purified bycolumn chromatography on silica gel eluting with 0-50% EtOAc in PE toafford title compound (3.0 g, 54.9% Yield) as colorless oil.

¹H NMR (400 MHz, CDCl₃,) δ=8.65 (s, 1H), 8.45 (s, 1H), 6.02 (s, 1H),5.47 (s, 1H), 2.21 (s, 3H).

2. Synthesis of 2-chloro-6-isopropyl-pyrazine

Add palladium on activated carbon (500 mg, 10 mass %) to2-chloro-6-isopropenyl-pyrazine (5.00 g, 19.4 mmol, 60 mass %) in ethylacetate (40 mL) under N₂. It is stirred at 20° C. under molecularhydrogen (15 psi) for 12 hours. The solid is filtered off. The mixtureis evaporated to afford the crude. The residue is purified by flashchromatography eluting with petroleum ether:EtOAc (3:1) to afford titlecompound (1.56 g, 45% Yield) as colorless oil. LCMS (m/z): 156.8 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ=8.42 (s, 1H), 8.38 (s, 1H), 3.14-3.05 (m,1H), 1.34 (d, J=7.2 Hz, 6H).

PREPARATION 6 2-tert-butoxy-6-chloro-pyrazine

Add 2,6-dichloropyrazine (2.0 g, 13 mmol) in THF (20 mL) to potassiumtert-butoxide (1.0 g, 8.8 mmol) at 0° C., the reaction mixture isstirred at 0° C. for 20 min, then the reaction mixture is stirred at 20°C. for 18 hours. The reaction mixture is poured into a saturated NH₄Clsolution (100 mL) and extracted with EtOAc (50 mL×2). The combinedorganic layers are washed with brine, dried over sodium sulfate andconcentrated. The residue is purified by flash chromatography elutingwith petroleum ether:EtOAc (3:1) to afford title compound (2.18 g, 86%)as white solid. LCMS (m/z): 131.2 [M-CH₂=C(CH₃)₂+H]⁺.

PREPARATION 7 2-chloro-6-(cyclobutoxy)pyrazine

Add cyclobutanol (2.00 g, 17.0 mmol) to sodium hydride (0.5 g, 19.8mmol, 60 mass %) in tetrahydrofuran (20 mL) at 0° C. and the reactionmixture is stirred at 20° C. for 30 min. then 2,6-dichloropyrazine (2.0g, 13.0 mmol) is added and the mixture is stirred at 20° C. for 12 h.The reaction mixture is poured into saturated NH₄Cl (30 mL). The resultmixture is extracted with EtOAc (30 mL×3). The combined organic phasesare washed with water (30 mL), brine (30 mL), dried over anhydroussodium sulfate, filtered and concentrated to afford title compound (2.1g, 87%) as a white solid. LCMS (m/z): 185.2 [M+H]⁺.

PREPARATION 8 2-chloro-6-(3, 3-difluorocyclobutoxy)pyrazine

Add 3,3-difluorocyclobutanol (2.00 g, 17.0 mmol) to sodium hydride (0.5g, 19.8 mmol, 60 mass %) in tetrahydrofuran (20 mL) at 0° C., then themixture is stirred at 20° C. for 30 min, 2,6-dichloropyrazine (2.0 g,13.0 mmol) is added and the mixture is stirred at 20° C. for 12 h. Thereaction mixture is poured into saturated NH₄Cl (30 mL). The resultmixture is extracted with EtOAc (30 mL×3). The combined organic phasesare washed with water (30 mL), brine (30 mL), dried over anhydroussodium sulfate, filtered and concentrated to afford the title compound(2.4 g, 85%). LCMS (m/z): 221.1 [M+H]⁺.

PREPARATION 9 2-chloro-6-(1-methoxy-1-methyl-ethyl)pyrazine

1. Synthesis of 2-(6-chloropyrazin-2-yl)propan-2-ol

Add methylmagnesium bromide (3 mol/L) in ether (28.7 mL, 86.1 mmol, 3mol/L) to a solution of methyl 6-chloropyrazine-2-carboxylate (5.00 g,28.7 mmol) in tetrahydrofuran (40 mL) at 0° C. and the mixture isstirred at 0° C. for 2 hours. The reaction is quenched with 1.0 M HClsolution (50 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over anhydroussodium sulfate, concentrated to afford a yellow oil. The yellow oil waspurified by flash chromatography eluting with petroleum ether/EtOAc(3:1) to afford title compound (600 mg, 11.5%) as brown oil.

2. Synthesis of 2-chloro-6-(1-methoxy-1-methyl-ethyl)pyrazine

Add sodium hydride (0.0792 g, 1.98 mmol, 60 mass %) to a solution of2-(6-chloropyrazin-2-yl)propan-2-ol (180 mg, 0.991 mmol) in DMF (1 mL)at 0° C., and the mixture is stirred for 30 min, then iodomethane (0.213g, 1.49 mmol) is added to the solution and the mixture is stirred at 20°C. for 2 h. The reaction is quenched with water (20 mL) and extractedwith EtOAc (20 mL×3). The combined organic layers are washed with brine(30 mL), dried over anhydrous sodium sulfate and concentrated to affordtitle compound (150 mg, 77.1%) as brown oil.

¹H NMR (400 MHz, CDCl₃) δ=8.75 (s, 1H), 8.48 (s, 1H), 3.25 (s, 3H), 1.57(s, 6H).

PREPARATION 10 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine

1. Synthesis of (E)-2-(5-bromo-2-pyridyl)-3-ethoxy-prop-2-enenitrile

Add 2-(5-bromo-2-pyridyl)acetonitrile (5.00 g, 25.1 mmol) in triethylorthoformate (30 mL) to acetic anhydride (7.93 g, 75.4 mmol) and themixture is stirred at 125° C. for 36 h. The reaction mixture isconcentrated to afford the title compound (5.6 g, 88%) as a brown crudewithout further purification for next step. LCMS (m/z): 253.1 [M+H]⁺.

2. Synthesis of 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine

Add (E)-2-(5-bromo-2-pyridyl)-3-ethoxy-prop-2-enenitrile (5.5 g, 21.8mmol) in ethanol (10 mL) to methylhydrazine (10 mL). The reactionmixture is heated to 100° C. and stirred for 3 hours. Then the reactionmixture is concentrated and purified by flash chromatography elutingwith petroleum ether:EtOAc (3:1) to afford title compound (3.15 g,57.1%). LCMS (m/z): 254.8/256.8 [M+H, Br⁷⁹/Br⁸¹]⁺.

PREPARATION 11N-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropoxy-pyrazin-2-amine

Add sodium hydride (0.585 g, 14.6 mmol, 60 mass %) to a solution of4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (1.30 g, 4.88 mmol) inDMF (15 mL). The reaction mixture is heated to 50° C. and then2-chloro-6-isopropoxy-pyrazine (0.975 g, 5.37 mmol) is added. Thereaction mixture is stirred at 50° C. for 3 hours. The reaction mixtureis poured into ammonium chloride solution (20 ml) and extracted withEtOAc (30 mL×2). The combined organic layers are washed with brine (20mL×2), dried over sodium sulfate and concentrated to afford the crude.The residue is purified by column chromatography (0-80% EA in PE) togive title compound (1.20 g, 60.0%) as a yellow oil. LCMS (m/z):389.0/390.8 [M+H, Br⁷⁹/B⁸¹]⁺.

EXAMPLE 1A Methyl1-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate 1.Synthesis of Methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate

Add 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.9 g, 3.56 mmol %),sodium carbonate (0.754 g, 7.11 mmol),1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate(1.19 g, 3.73 mmol) in in 1,4-dioxane (10.0 mL) and water (2 mL) to[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.266 g,0.356 mmol) under N₂. Then the reaction mixture is stirred at 100° C.for 4 h under N₂. The reaction mixture is concentrated to give a blacksolid, which is purified by flash chromatography eluting withEtOAc:CH₂Cl₂ (1:1) to afford title compound (1.1 g, 89.2%) as a brownsolid. LCMS (m/z): 348.9 [M+H]⁺.

2. Synthesis of Methyl1-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (116 mg, 0.123 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (110 mg, 0.185 mmol) toa solution of methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate(430 mg, 1.23 mmol), 2-tert-butoxy-6-chloro-pyrazine (254 mg, 1.23 mmol)and cesium carbonate (1.21 g, 3.7 mmol) in O₂-free 1,4-dioxane (4 mL) at25° C. The mixture is then stirred at 100° C. for 6 hr. The mixture isfiltered through a pad of silica gel and the filtrate is concentrated.The residue is purified by flash chromatograph eluting with PE/EtOAc(1:1) to afford the title compound (160 mg, 25%). LCMS (m/z): 499.3[M+H]⁺.

EXAMPLE 1B1-[4-[-6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid

Add lithium hydroxide monohydrate (200 mg, 8.1 mmol) to methyl1-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate (160 mg, 0.32 mmol) in MeOH (3 mL) and water (3mL). The resulting mixture is stirred for 12 hours 25° C. The mixture isconcentrated and diluted with water (5 mL). The mixture is acidifiedwith HCl (1M) to pH=4-6. The mixture is extracted with DCM (5 mL×5). Thecombined organic phases are washed with brine (10 mL), concentrated,purified by prep-HPLC [Column SunFire C18, 5 μm, 30×100 mm Condition:water (0.1% FA)-ACN Begin B 29 End B 44 Gradient Time (min) 10 100% BHold Time (min) 9.0 FlowRate (ml/min) 30] to afford the title compound(100 mg, 64%) as yellow solid.

LCMS (m/z): 485.3 [M+H]⁺.

¹H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.80 (s, 1H), 8.08 (s, 1H),7.98 (m, 1H), 7.76 (s, 1H), 7.83 (s, 1H), 7.60-7.57 (m, 3H), 7.54 (s,1H), 7.43-7.40 (m, 3H), 3.67 (s, 3H), 1.48 (m, 2H), 1.23-1.23 (s, 9H),1.15 (m, 2H).

EXAMPLE 2A Methyl1-[4-[6-[5-[[6-(cyclobutoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Under O₂ free condition, add tris(dibenzylideneacetone)dipalladium (116mg, 0.123 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (110mg, 0.185 mmol) to the 1,4-dioxane (4 mL) solution of methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate (430 mg, 1.23 mmol) (prepared according to Example 1A),2-chloro-6-(cyclobutoxy)pyrazine (250 mg, 1.36 mmol) and cesiumcarbonate (1.21 g, 3.7 mmol)), stirred at 100° C. for 6 hr. The mixtureis filtered through a pad of silica gel (200-300 mush) and the filtrateis concentrated. The residue is purified by flash chromatograph elutingwith petroleum ether:EtOAc (1:1) to afford the title compound (260 mg,41%). LCMS (m/z): 497.3 [M+H]⁺.

EXAMPLE 2B1-[4-[6-[5-[[6-(cyclobutoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid

Add lithium hydroxide monohydrate (200 mg, 8.1 mmol) to a solution ofmethyl1-[4-[6-[5-[[6-(cyclobutoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(260 mg, 0.51 mmol) in MeOH (3 mL) and water (3 mL) and the mixture isstirred for 12 hours 25° C. The mixture is concentrated and diluted withwater (5 mL). The mixture is acidified with HCl (1M) to pH=4˜6. Themixture is extracted with DCM (5 mL×5). The combined organic phases arewashed with brine (10 mL), concentrated and then purified by prep-HPLC[Column SunFire C18, 5 μm, 30×100 mm Condition: water (0.1% FA)-ACNBegin B 29 End B 44 Gradient Time (min) 10 100% B Hold Time (min) 8.5FlowRate (ml/min) 30] to afford the title compound (50 mg, 23%) asyellow solid. LCMS (m/z): 483.3 [M+H]⁺.

¹H NMR (500 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (s, 1H), 8.80 (s, 1H),8.08 (s, 1H), 8.00 (m, 1H), 7.79 (s, 1H), 7.63-7.57 (m, 3H), 7.54 (s,1H), 7.41 (m, 2H), 4.63 (m, 1H) 3.68 (s, 3H), 2.11 (m, 2H), 2.02 (m,2H). 1.68 (m, 1H), 1.49 (m, 1H), 1.46 (m, 2H), 1.14 (m, 2H).

EXAMPLE 3A Methyl1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate 1.Synthesis of 2-(5-chloro-3-fluoro-2-pyridyl)acetonitrile

Add n-butyllithium in hexanes (110 g, 381 mmol, 2.5 mol/L) to a solutionof acetonitrile (17.2 g, 419 mmol) in anhydrous THF (50 mL) at −78° C.under nitrogen. The mixture is stirred at −78° C. for 30 min. Then addedwith a solution of 5-chloro-2,3-difluoro-pyridine (60.0 g, 381 mmol) inTHF (100 mL) and the mixture is stirred at −78° C. for 2 h. The reactionmixture is warmed to 20° C. and stirred for 1 h. The reaction mixture isquenched with sat. NH₄Cl (300 mL). The reaction mixture is extractedwith EtOAc (200 mL×3). The combined organic phases are washed with water(100 mL), brine (100 mL), concentrated to afford a yellow residue, whichis purified by column chromatography on silica gel eluting with PE:EtOAc(10:1) to afford title compound2-(5-chloro-3-fluoro-2-pyridyl)acetonitrile (20.0 g, 30.8%) as a yellowoil. LCMS (m/z): 170.8 [M+H]⁺.

2. Synthesis of(Z)-2-(5-chloro-3-fluoro-2-pyridyl)-3-ethoxy-prop-2-enenitrile

Add 2-(5-chloro-3-fluoro-2-pyridyl)acetonitrile (20.0 g, 117 mmol) inacetic anhydride (47.9 g, 469 mmol) to triethyl orthoformate (100 mL)and the mixture is stirred at 125° C. for 36 h. The reaction mixture isconcentrated to afford title compound(Z)-2-(5-chloro-3-fluoro-2-pyridyl)-3-ethoxy-prop-2-enenitrile (45.7 g,117 mmol, 58 mass %, 99.5%) as a brown oil. it is used for the next stepdirectly without further purification. LCMS (m/z): 226.9 [M+H]⁺.

3. Synthesis of 4-(5-chloro-3-fluoro-2-pyridyl)-2-methyl-pyrazol-3-amine

Add methylhydrazine (40.4 g, 351 mmol, 40 mass %) to a solution of2-(5-chloro-3-fluoro-2-pyridyl)-3-ethoxy-prop-2-enenitrile (45.7 g, 117mmol, 58 mass %) in ethanol (100 mL), and the reaction mixture isstirred at 100° C. for 3 h. The reaction mixture is concentrated andpurified by column chromatography on silica gel eluting with PE:EtOAc(1:1) to afford title (5.50 g, 19.7%) as a brown solid. LCMS (m/z):226.9 [M+H]⁺.

4. Synthesis of Methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate

Add Pd₂(dba)₃ (0.576 g, 0.629 mmol) and tricyclohexylphosphine (0.184 g,0.629 mmol) to sodium carbonate (1.33 g, 12.6 mmol), methyl,1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate (1.55 g, 4.61 mmol, 90 mass %) and4-(5-chloro-3-fluoro-2-pyridyl)-2-methyl-pyrazol-3-amine (1.00 g, 4.19mmol) in 1,4-dioxane (16 mL) and water (4 mL), then the reaction mixtureis stirred at 90° C. for 1 h under nitrogen. The reaction mixture isconcentrated to afford a black residue, which is purified by columnchromatography on silica gel eluting with PE:EtOAc (2:3) to afford title(1.20 g, 74.2%) as a brown solid. LCMS (m/z): 367.1 [M+H]⁺.

5. Synthesis of Methyl1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate

Add Pd₂(dba)₃ (0.107 g, 0.117 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0675 g, 0.117 mmol)to a solution of methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate(300 mg, 0.778 mmol), 2-chloro-6-(cyclopropoxy)pyrazine (0.168 g, 0.933mmol) and cesium carbonate (0.760 g, 2.33 mmol) in 1,4-dioxane (3 mL),then the reaction mixture is stirred at 90° C. for 1 h under nitrogen.The reaction mixture is concentrated and purified by columnchromatography on silica gel eluting with PE:EtOAc (1:2) to afford titlecompound (320 mg, 87% mass, 71.5%) as a yellow solid. LCMS (m/z): 501.2[M+H]⁺.

EXAMPLE 3B1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (0.0461 g, 1.04 mmol) to a solution ofmethyl1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate(300 mg, 0.521 mmol, 87 mass %) in methanol (1 mL) and water (1 mL), andthe mixture is stirred at 60° C. for 1 h. then the reaction mixture isacidified by 1N HCl to pH=6 and removed the solvent. The crude productis purified by prep-HPLC [column: YMC-ActusTriart C18 150×30 mm×5 μm,condition: 55-85% B (A: water/0.05% HCl, B: CH3CN), flow rate: 25mL/min] and lyophilized to afford title compound (153.0 mg, 55.3%) as ayellow solid. LCMS (m/z): 487.1 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ=8.65 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.95 (brd, J=12.0 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.60 (s, 1H),7.49 (d, J=8.0 Hz, 2H), 3.99-3.92 (m, 1H), 3.86 (s, 3H), 1.64-1.58 (m,2H), 1.25-1.20 (m, 2H), 0.70-0.58 (m, 4H).

EXAMPLE 4A Methyl1-[4-[5-fluoro-6-[5-[[6-(1-fluoro-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add cesium carbonate (1.18 g, 3.63 mmol) and Pd₂(dba)₃ (85.7 mg, 0.0907mmol) to methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate (350 mg, 0.907 mmol) (prepared according toExample 3A), 2-chloro-6-(1-fluoro-1-methyl-ethyl)pyrazine (220 mg, 1.13mmol, 90 mass %) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(81.0 mg, 0.136 mmol) in 1,4-dioxane (5 mL) under N₂. The mixture isstirred at 100° C. for 12 hours. The reaction is quenched with water (20mL) and extracted with EtOAc (20 mL×3). The combined organic layers arewashed with brine (30 mL), dried over anhydrous sodium sulfate andconcentrated to afford crude product. The residue is purified by columnchromatography eluting with 0-80% EtOAc in PE to afford title product(350 mg, 60 mass %, 45.9%) as brown oil. LCMS (m/z): 505.1 [M+H]⁺.

EXAMPLE 4B1-[4-[5-fluoro-6-[5-[[6-(1-fluoro-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid Hydrochloride

Add lithium hydroxide hydrate (53.5 mg, 1.25 mmol) to methyl1-[4-[5-fluoro-6-[5-[[6-(1-fluoro-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(350 mg, 0.416 mmol, 60 mass %) in tetrahydrofuran (5 mL) and water (0.5mL). The reaction is stirred at 50° C. for 14 hours. The mixture isadjusted to pH=5-6 with 1 N HCl, extracted with EtOAc (40 mL×3). Thecombined organic layers are washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated. The crude product is purified byprep-HPLC [Column YMC-Actus Triart C18 100×30 mm×5 μm Condition: water(0.05% HCl)-ACN Begin B 50 End B 80 Gradient Time (min) 9.5 100% B HoldTime (min) 2.5 FlowRate (ml/min) 25] to afford the title product (116mg, 51.6%) as a yellow solid. LCMS (m/z): 491.1 [M+H]⁺.

¹H NMR (400 MHz, MeOD): δ=8.71 (d, J=1.6 Hz, 1H), 8.25 (s, 1H), 8.20(dd, J=11.6, 2.0 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.67 (d,J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 3.89 (s, 3H), 1.68-1.61 (m, 2H),1.44 (d, J=22.0 Hz, 6H), 1.29-1.22 (m, 2H).

EXAMPLE 5A Methyl1-[4-[6-[5-[[6-(3,3-difluorocyclobutoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (116 mg, 0.123 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (110 mg, 0.185 mmol))and cesium carbonate (1.21 g, 3.7 mmol) to a solution of methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate(530 mg, 1.52 mmol) (prepared according to Example 1A) and2-chloro-6-(cyclobutoxy)pyrazine (250 mg, 1.36 mmol) in O₂-free1,4-dioxane (4 mL) at 25° C. The mixture is stirred at 100° C. for 6 hr.The mixture is filtered through a pad of silica gel (200-300 mush) andthe filtrate is concentrated. The residue is purified by flashchromatograph eluting with petroleum ether:EtOAc (1:1) to afford thetitle compound (260 mg, 41%). LCMS (m/z): 497.3 [M+H]⁺.

EXAMPLE 5B1-[4-[6-[5-[[6-(3,3-difluorocyclobutoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid

Add lithium hydroxide monohydrate (200 mg, 8.1 mmol) to a solution ofmethyl1-[4-[6-[5-[[6-(3,3-difluorocyclobutoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(260 mg, 0.51 mmol) in MeOH (3 mL) and water (3 mL). The resultingmixture is stirred for 12 hours 25° C. The mixture is concentrated anddiluted with water (5 mL). The mixture is acidified with HCl (1M) topH=4-6 and extracted with DCM (5 mL×5). The combined organic phases arewashed with brine (10 mL), concentrated, and purified by prep-HPLC[Column SunFire C18, 5 μm, 30×100 mm Condition: water (0.1% FA)-ACNBegin B 29 End B 44 Gradient Time (min) 10 100% B Hold Time (min) 8.5FlowRate (ml/min) 30] to afford the title compound (50 mg, 23%) asyellow solid. LCMS (m/z): 483.3 [M+H]⁺.

¹H NMR (500 MHz, DMSO-d6) δ=9.41 (s, 1H), 8.79 (m, 1H), 8.80 (s, 1H),8.10 (s, 1H), 7.99 (m, 1H), 7.86 (s, 1H), 7.63-7.58 (m, 4H), 7.43 (m,2H), 4.61 (m, 1H) 3.69 (s, 3H), 2.79 (m, 2H), 2.57 (m, 2H). 1.45 (m,2H), 1.14 (m, 2H).

EXAMPLE 6A Methyl1-[4-[6-[5-[[6-(1-methoxy-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (0.0384 g, 0.0407 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0364 g, 0.0611 mmol)and cesium carbonate (0.398 g, 1.22 mmol) to a solution of methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate(0.142 g, 0.387 mmol), 2-chloro-6-(1-methoxy-1-methyl-ethyl)pyrazine(80.0 mg, 0.407 mmol) in 1,4-dioxane (4 mL) under N₂. The mixture isstirred at 100° C. for 4 hours. The reaction is quenched with water (20mL) and extracted with EtOAc (20 mL×3). The combined organic layers arewashed with brine (30 mL), dried over anhydrous sodium sulfate andconcentrated to afford crude. The residue is purified by flashchromatography eluting with petroleum ether/EtOAc (1:5) to afford titlecompound (90 mg, 44.3%) as brown oil. LCMS (m/z): 521.1[M+Na]⁺.

EXAMPLE 6B1-[4-[6-[5-[[6-(1-methoxy-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide (11.4 mg, 0.271 mmol) to a solution of methyl1-[4-[6-[5-[[6-(1-methoxy-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(90 mg, 0.181 mmol) in tetrahydrofuran (4 mL) and water (4 mL) at roomtemperature. The mixture is stirred at 60° C. for 2 hours. The mixtureis extracted with EtOAc (10 mL×3) and the aqueous is adjusted to pH=5-7with HCl (1M). The mixture is extracted with EtOAc (30 mL×3). Thecombined organic layers are washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and evaporated to afford the crude. It ispurified by pre-HPLC [Column Boston Green ODS 150*30, 5 Condition water(0.05% HCl)-ACN Begin B 35 End B 65 Gradient Time (min) 3 100% B HoldTime (min) 1.66 FlowRate (ml/min) 25] to afford title compound (44.1 mg,45.3%) as a yellow solid. LCMS (m/z): 485.2 [M+H]⁺.

¹H NMR (DMSO-d6, 400 MHz) δ=9.99 (s, 1H), 8.85 (s, 1H), 8.43 (d, J=7.2Hz, 1H), 8.27 (d, J=4.4 Hz, 2H), 8.09 (s, 1H), 7.81 (d, J=8.4 Hz, 1H),7.68 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 3.78 (s, 3H), 2.92 (s,3H), 1.52-1.45 (m, 2H), 1.22-1.09 (m, 2H), 1.09 (s, 6H).

EXAMPLE 7A Ethyl1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-methyl-phenyl]cyclopropanecarboxylate 1.Synthesis of Ethyl 2-(4-bromo-2-methyl-phenyl)acetate

Add sulfuric acid (3.68 g, 2 mL) to a mixture of2-(4-bromo-2-methyl-phenyl)acetic acid (2.00 g, 8.73 mmol) in ethanol(20 mL), then the reaction mixture is stirred at 80° C. for 2 h. Thereaction mixture is cooled to 20° C. and poured into water (100 mL). Theresulting mixture is neutralized by sat. Na₂CO₃ to pH=8. The mixture isextracted with EtOAc (30 mL×3). The combined organic phases are washedwith water (20 mL) and brine (20 mL), dried over anhydrous sodiumsulfate, concentrated to afford title compound (2.30 g, 97.3%) as ayellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.34 (s, 1H), 7.29 (dd, J=2.0, 8.4 Hz,1H), 7.07 (d, J=8.4 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.58 (s, 2H), 2.30(s, 3H), 1.25 (t, J=7.2 Hz, 3H)

2. Synthesis of Ethyl 1-(4-bromo-2-methyl-phenyl)cyclopropanecarboxylate

Add sodium hydride (60 mass %) in oil (0.296 g, 7.39 mmol, 60 mass %) toa mixture of ethyl 2-(4-bromo-2-methyl-phenyl)acetate (1.00 g, 3.69mmol) in DMF (5 mL). The mixture is stirred at 20° C. for 0.5 h, then1,2-dibromoethane (0.764 g, 4.06 mmol) is added and stirred at 20° C.for 2 h. The reaction mixture is quenched with sat. NH₄Cl (10 mL). Theresult mixture is extracted with EtOAc (10 mL×3). The combined organicphases are washed with water (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated, then purified by columnchromatography on silica gel eluting with PE:EtOAc (10:1) to affordtitle compound (100 mg, 9.08%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.32 (d, J=1.6 Hz, 1H), 7.27 (dd, J=1.6, 8.4Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 2.30 (s, 3H),1.70-1.65 (m, 2H), 1.16 (t, J=7.2 Hz, 3H), 1.14-1.09 (m, 2H)

3. Synthesis of Ethyl1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-methyl-phenyl]cyclopropanecarboxylate

Add Pd(dppf)Cl₂ (0.0225 g, 0.0302 mmol) and potassium acetate (0.0916 g,0.906 mmol) to a solution of ethyl1-(4-bromo-2-methyl-phenyl)cyclopropanecarboxylate (90.0 mg, 0.302mmol), bis(pinacolato)diboron (0.0861 g, 0.332 mmol) in 1,4-dioxane (0.5mL), then the reaction mixture is stirred at 90° C. for 1 h undernitrogen.N-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropoxy-pyrazin-2-amine(0.136 g, 0.332 mmol), sodium carbonate (0.0960 g, 0.906 mmol) and water(0.1 mL) is added to above solution and stirred at 90° C. for 1 h undernitrogen. The reaction mixture is concentrated to afford a blackresidue, which is purified by column chromatography on silica geleluting with PE:EtOAc (1:1) to afford title compound (90 mg, 58.0%) as ayellow oil. LCMS (m/z): 513.2 [M+H]⁺.

EXAMPLE 7B1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-methyl-phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (0.0137 g, 0.323 mmol) to a mixture ofethyl1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-methyl-phenyl]cyclopropanecarboxylate(90 mg, 0.162 mmol) in methanol (1 mL) and water (1 mL), then thereaction mixture is stirred at 60° C. for 2 h. The reaction mixture isacidified by 1 N HCl to pH=6 and extracted with EtOAc (30 mL×3), driedover anhydrous sodium sulfate, filtered and concentrated. The crudeproduct is purified by prep-HPLC [column: YMC-ActusTriart C18 150×30mm×5 μm, condition: 30-60% B (A: water/0.05% HCl, B: CH3CN), flow rate:25 mL/min] and lyophilized to afford title compound (17.9 mg, 20.5%) asa yellow solid. LCMS (m/z): 485.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ=8.90 (d, J=2.0 Hz, 1H), 8.71 (dd, J=2.0, 8.8Hz, 1H), 8.27 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.81 (br s, 1H),7.62-7.57 (m, 2H), 7.54 (dd, J=2.0, 8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H),4.78-4.67 (m, 1H), 3.87 (s, 3H), 2.46 (s, 3H), 1.74-1.66 (m, 2H),1.25-1.17 (m, 2H), 1.12 (d, J=6.4 Hz, 6H).

EXAMPLE 8A Ethyl1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate 1.Synthesis of 2-[4-bromo-2-(trifluoromethyl)phenyl]acetic Acid

Add hydrochloric acid (2 mL, 12 M) to a solution of2-[4-bromo-2-(trifluoromethyl)phenyl]acetonitrile (600 mg, 2.25 mmol) inacetic acid (2 mL), the mixture is stirred at 100° C. for 2 h undernitrogen. The reaction mixture is concentrated to afford title compound(600 mg, 89.5%) as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.82 (d, J=1.6 Hz, 1H), 7.67 (dd, J=1.6, 8.4Hz, 1H), 7.29 (s, 1H), 3.83 (s, 2H).

2. Synthesis of Ethyl 2-[4-bromo-2-(trifluoromethyl)phenyl]acetate

Add sulfuric acid (3.68 g, 2 mL) to a solution of2-[4-bromo-2-(trifluoromethyl)phenyl]acetic acid (600 mg, 2.0 mmol) inethanol (10 mL), the mixture is stirred at 80° C. for 3 h undernitrogen. The reaction mixture is diluted with water (20 mL) andextracted with EtOAc (20 mL×2). The combined organic layers are washedwith sat. NaHCO₃ (20 mL), brine (20 mL×2), dried over sodium sulfate andconcentrated to afford title compound (600 mg, 91.0%) as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.80 (d, J=1.6 Hz, 1H), 7.66 (dd, J=1.6, 8.0Hz, 1H), 7.28 (d, J=9.2 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.77 (s, 2H),1.25 (t, J=7.2 Hz, 3H).

3. Synthesis of Ethyl 1-[4-bromo-2-(trifluoromethyl)phenyl]cyclopropaneCarboxylate

Add sodium hydride in paraffin oil (0.148 g, 3.69 mmol, 60 mass %) to asolution of ethyl 2-[4-bromo-2-(trifluoromethyl)phenyl]acetate (550 mg,1.68 mmol) in DMF (5 mL), then the mixture is heated to 50° C. for 1hour. 1, 2-dibromoethane (0.335 g, 1.76 mmol) is added and the reactionis stirred at 50° C. for 2 hours. The reaction is quenched withsaturated NH₄Cl solution (30 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers are washed with brine (30 mL), dried overanhydrous sodium sulfate, filtered and concentrated. The residue ispurified by flash chromatography eluting with petroleum ether/EtOAc(20:1) to afford the crude. The crude is purified by pre-HPLC [column:Boston Green ODS 150×30, 5 μm. condition: 35-65% B (A: water (0.05%HCl), B: ACN), flow rate: 25 mL/min] to afford title compound (0.150 g,25.2%) as colorless oil. LCMS (m/z): 336.9/338.8 [M+H, Br⁷⁹/Br⁸¹]⁺.

¹H NMR (400 MHz, CDCl₃) δ=7.78 (d, J=2.0 Hz, 1H), 7.63 (dd, J=1.6, 8.4Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.13-3.96 (m, 2H), 1.65-1.58 (m, 2H),1.33-1.19 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).

4. Synthesis of Ethyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate

Add Pd(dppf)Cl₂ (0.0316 g, 0.0423 mmol) and potassium acetate (0.128 g,1.27 mmol) to a solution of ethyl1-[4-bromo-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate (150 mg,0.423 mmol), bis(pinacolato)diboron (0.120 g, 0.465 mmol) in 1,4-dioxane(4 mL), then the reaction mixture is stirred at 90° C. for 1 h undernitrogen. Then 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.124 g,0.465 mmol), sodium carbonate (0.134 g, 1.27 mmol) and water (1 mL) isadded to above solution and stirred at 90° C. for 1 h under nitrogen.The reaction mixture is concentrated to afford a black residue, which ispurified by column chromatography on silica gel eluting with PE:EtOAc(1:1) to afford title compound (140 mg, 77.6%) as a yellow oil. LCMS(m/z): 431.1 [M+H]⁺.

5. Synthesis of Ethyl1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (0.0300 g, 0.0328 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0190 g, 0.0328 mmol)and cesium carbonate (0.320 g, 0.984 mmol) to a mixture of ethyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate(140 mg, 0.328 mmol), 2-chloro-6-(cyclopropoxy)pyrazine (0.0706 g, 0.393mmol) in 1,4-dioxane (5 mL), then the reaction mixture is stirred at 95°C. for 2 h under nitrogen. The reaction mixture is concentrated andpurified by column chromatography on silica gel eluting with PE:EtOAc(4:1) to afford title compound (133 mg, 72.0%) as a yellow solid. LCMS(m/z): 565.1 [M+H]⁺.

EXAMPLE 8B1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (0.0187 g, 0.446 mmol) to a mixture ofethyl1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate(133 mg, 0.223 mmol) in methanol (2 mL) and water (2 mL), then thereaction mixture is stirred at 60° C. for 1 h. The reaction mixture isacidified by 1N HCl to pH=6, then purified by prep-HPLC [column:YMC-Actus Triart C18 150*30 mm*5 μm, condition: 40-70% B (A: water/0.05%HCl, B: CH3CN), flow rate: 25 mL/min] and lyophilized to afford titlecompound (34.4 mg, 25.3%) as a white solid. LCMS (m/z): 537.0 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ=9.01 (d, J=2.0 Hz, 1H), 8.76 (dd, J=2.4, 8.8Hz, 1H), 8.27 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.09 (s, 1H), 8.00 (dd,J=1.6, 8.0 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.70 (s, 1H),3.91-3.84 (m, 4H), 1.97-1.54 (m, 2H), 1.54-1.08 (m, 2H), 0.65-0.55 (m,4H)

EXAMPLE 9A Ethyl1-[2-cyano-4-[[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate 1.Synthesis of 2-(4-bromo-2-cyano-phenyl)acetate

Add chlorotrimethylsilane (0.233 g, 2.10 mmol) to a mixture of zinc(2.55 g, 39.0 mmol) in tetrahydrofuran (20 mL) at 15° C. The mixture isstirred for 15 min and then a solution of ethyl bromoacetate (5.11 g,30.0 mmol) in tetrahydrofuran (10 mL) is added dropwise. The reaction isheated to 40° C. for 30 min. The mixture is cooled to 20° C. and thesupernatant liquid is used as title compoundbromo-(2-ethoxy-2-oxo-ethyl)zinc (30 mmol, 1 mol/L, 100%) in the nextstep directly. Add bromo-(2-ethoxy-2-oxo-ethyl)zinc (15.4 mL, 15.4 mmol,1 mol/L) to a mixture of 5-bromo-2-iodo-benzonitrile (4.00 g, 12.9mmol), bis(dibenzylideneacetone)palladium (0.187 g, 0.322 mmol,) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.188 g, 0.322 mmol) intetrahydrofuran (10 mL) under nitrogen. The reaction is heated to 65° C.for 12 hours. The reaction is quenched with saturated NH₄Cl solution (30mL) and extracted with EtOAc (30 mL×3). The combined organic layers arewashed with brine (30 mL), dried over anhydrous sodium sulfate, filteredand concentrated. The residue is purified by flash chromatographyeluting with petroleum ether/EtOAc (10:1) to the title compound (0.520g, 14.3%) as a light grey solid.

¹H NMR (400 MHz, CDCl₃) δ=7.80 (d, J=2.0 Hz, 1H), 7.70 (dd, J=2.0, 8.4Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.84 (s, 2H),1.29 (t, J=7.2 Hz, 3H).

2. Synthesis of Ethyl 1-(4-bromo-2-cyano-phenyl)cyclopropanecarboxylate

Add sodium hydride in paraffin oil (0.162 g, 4.05 mmol, 60 mass %) to asolution of ethyl 2-(4-bromo-2-cyano-phenyl)acetate (0.520 g, 1.84 mmol)in DMF (10 mL), and the mixture is heated to 50° C. for 1 hour. Then1,2-dibromoethane (0.367 g, 1.93 mmol) is added and the reaction isstirred at 50° C. for 3 hours. The reaction is quenched with saturatedNH₄Cl solution (30 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over anhydroussodium sulfate, filtered and concentrated. The residue is purified byflash chromatography eluting with petroleum ether/EtOAc (20:1) to affordtitle compound (0.370 g, 64.9%) as a grey solid.

¹H NMR (400 MHz, CDCl₃) δ=7.79 (d, J=2.0 Hz, 1H), 7.67 (dd, J=2.0, 8.4Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 1.85-1.79 (m,2H), 1.29-1.24 (m, 2H), 1.20 (t, J=7.2 Hz, 3H).

3. Synthesis of Ethyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-2-cyano-phenyl]cyclopropanecarboxylate

Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0482g, 0.0646 mmol) to a mixture of ethyl1-(4-bromo-2-cyano-phenyl)cyclopropanecarboxylate (200 mg, 0.646 mmol),bis(pinacolato)diboron (0.184 g, 0.711 mmol) and potassium acetate(0.196 g, 1.94 mmol) in 1,4-dioxane (4 mL), then the reaction mixture isstirred at 90° C. for 1 h under nitrogen. Then4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.189 g, 0.711 mmol),sodium carbonate (0.205 g, 1.94 mmol) and water (1 mL) are added toabove solution and stirred at 90° C. for 1 h under nitrogen. Thereaction mixture is concentrated to afford a black residue, which ispurified by column chromatography on silica gel eluting with PE:EtOAc(1:1) to afford title compound (230 mg, 87.3%) as a yellow solid. LCMS(m/z): 388.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ=8.68 (d, J=2.4 Hz, 1H), 7.86 (d, J=1.6 Hz,1H), 7.80 (dd, J=2.4, 8.4 Hz, 1H), 7.76-7.71 (m, 2H), 7.49 (dd, J=1.6,8.4 Hz, 2H), 5.62 (br s, 2H), 4.17 (q, J=7.2 Hz, 2H), 3.71 (s, 3H),1.88-1.81 (m, 2H), 1.36-1.30 (m, 2H), 1.22 (t, J=7.2 Hz, 3H).

4. Synthesis of Ethyl1-[2-cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium(0) (0.0695 g, 0.0736 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0434 g, 0.0736 mmol)to a mixture of ethyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-2-cyano-phenyl]cyclopropanecarboxylate(200 mg, 0.490 mmol), 2-chloro-6-(cyclopropoxy)pyrazine (0.106 g, 0.589mmol) and cesium carbonate (0.479 g, 1.47 mmol,) in 1,4-dioxane (5 mL,then the reaction mixture is stirred at 95° C. for 2 h under nitrogen.The reaction mixture is concentrated to afford a black residue, which ispurified by column chromatography on silica gel eluting with PE:EtOAc(1:4) to afford title compound (200 mg, 63 mass %, 49.3%) as a yellowsolid. LCMS (m/z): 522.1 [M+H]⁺.

EXAMPLE 9B1-[2-cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (0.0203 g, 0.483 mmol) to a mixture ofethyl1-[2-cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(200 mg, 0.242 mmol, 63 mass %) in methanol (2 mL) and water (2 mL, thenthe reaction mixture is stirred at 60° C. for 1 h. The reaction mixtureis acidified by 1N HCl to pH=6 and is concentrated. Then purified byprep-HPLC [column: YMC-Actus Triart C18 150×30 mm×5 μm, condition:35-65% B (A: water/0.05% HCl, B: CH₃CN), flow rate: 25 mL/min] andlyophilized to afford title compound (49.6 mg, 92.44 mass %, 35.8%) as ayellow solid. LCMS (m/z): 494.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ=9.02 (s, 1H), 8.77 (d, J=7.2 Hz, 1H), 8.28 (s,1H), 8.22 (s, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.96(s, 1H), 7.79-7.67 (m, 2H), 3.99-3.80 (m, 4H), 1.86-1.75 (m, 2H),1.45-1.34 (m, 2H), 0.71-0.54 (m, 4H).

EXAMPLE 10A Methyl1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate (530 mg, 1.377 mmol) (prepared according to Example1A), 2-chloro-6-(cyclopropoxy)pyrazine (300 mg, 1.758 mmol) and cesiumcarbonate (1.0 g, 3.1 mmol) in O₂-free 1,4-dioxane (10 mL) totris(dibenzylideneacetone)dipalladium (300 mg, 0.33 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (280 mg, 0.483 mmol) at25° C. The mixture is then stirred at 100° C. for 6 hr. The mixture isfiltered through a pad of silica gel (200-300 mush) and the filtrate isconcentrated. The residue is purified by flash chromatograph elutingwith petroleum ether:EtOAc (1:1) to afford the title compound (300 mg,45.2%) as light yellow oil. LCMS (m/z): 483.2 [M+H]⁺.

EXAMPLE 10B1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid

Add methyl1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(300 mg, 0.621 mmol) in THF (4 mL) and water (2 mL) to lithium hydroxidemonohydrate (200 mg, 8.1 mmol). The resulting mixture is stirred for 12hours 25° C. The mixture is concentrated and diluted with water (5 mL).The mixture is acidified with HCl (1M) to pH=4-6. The mixture isextracted with DCM (5 mL×5). The combined organic phases are washed withbrine (10 mL), concentrated, purified by prep-HPLC [Column SunFire C18,5 μm, 30×100 mm Condition: water (0.1% FA)-ACN Begin B 29 End B 44Gradient Time (min) 10 100% B Hold Time (min) 7.5 FlowRate (ml/min) 30]to afford the title compound (50 mg, 42.1%) as yellow solid. LCMS (m/z):469.2 [M+H]⁺.

¹H NMR (500 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.80 (d, J=2.0 Hz, 1H),8.10-7.98 (M, 2H), 7.81 (s, 1H), 7.68 (s, 1H), 7.62-7.60 (m, 3H), 3.94(m, 1H), 3.70 (s, 3H), 1.45 (m, 2H), 1.13 (m, 2H), 0.60 (d, J=6.0 Hz,4H).

EXAMPLE 11A Methyl1-[4-[5-fluoro-6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (0.0712 g, 0.0778 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0450 g, 0.0778 mmol)and cesium carbonate (0.507 g, 3 1.56 mmol) to a solution of methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate(200 mg, 0.519 mmol) (prepared according to Example 3A),2-chloro-6-isopropoxy-pyrazine (0.113 g, 0.622 mmol) in 1,4-dioxane (3mL), then the reaction mixture is stirred at 90° C. for 1 h undernitrogen. The reaction mixture is concentrated and purified by columnchromatography on silica gel eluting with PE:EtOAc (1:2) to afford titlecompound (130 mg, 49.9%) as a yellow solid. LCMS (m/z): 503.2 [M+H]⁺.

EXAMPLE 11B1-[4-[5-fluoro-6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add hydroxide lithium hydrate (0.0217 g, 0.517 mmol) to a mixture ofmethyl1-[4-[5-fluoro-6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(200 mg, 0.259 mmol, 65 mass %) in methanol (1 mL) and water (1 mL) wasadded, then the reaction mixture is stirred at 60° C. for 1 h. Thereaction mixture was acidified by 1N HCl to pH=6. The result mixture isconcentrated and purified by prep-HPLC [column: YMC-ActusTriart C18150×30 mm×5 μm, condition: 48-78% B (A: water/0.05% HCl, B: CH₃CN), flowrate: 25 mL/min] and lyophilized to afford title compound (101.6 mg,99.69 mass %, 74.6%) as a yellow solid. LCMS (m/z): 489.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ=8.60 (s, 1H), 8.00 (d, J=2.8 Hz, 1H), 7.84(dd, J=2.0, 12.0 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.47 (d,J=8.4 Hz, 2H), 7.45 (br s, 1H), 4.86-4.83 (m, 1H), 3.84 (s, 3H),1.63-1.59 (m, 2H), 1.25-1.20 (m, 2H), 1.16 (d, J=6.4 Hz, 6H)

EXAMPLE 12A Methyl1-[4-[6-[5-[[6-(1,1-difluoroethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add to tris(dibenzylideneacetone)dipalladium (0.103 g, 0.109 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0976 g, 0.164 mmol)to methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate(0.400, 1.09 mmol) (prepared according to Example 1A),2-chloro-6-(1,1-difluoroethyl)pyrazine (0.325 g, 1.64 mmol, 90 mass %)and cesium carbonate (1.42 g, 4.36 mmol) in 1,4-dioxane (8 mL) under N₂.The mixture is stirred at 100° C. for 12 hours. The mixture is dilutedwith water (40 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layers are washed with brine (50 mL), dried over anhydroussodium sulfate, filtered and concentrated. The residue is purified bycolumn chromatography on silica gel EtOAc:PE (1:1) to afford title (361mg, 68.1%). LCMS (m/z): 491.1 [M+H]⁺.

EXAMPLE 12B1-[4-[6-[5-[[6-(1,1-difluoroethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (91.0 mg, 2.12 mmol) to a solution ofmethyl1-[4-[6-[5-[[6-(1,1-difluoroethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(360 mg, 0.706 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL). Thereaction is stirred at 50° C. for 14 hours. The mixture is adjusted topH=5-6 with 1 N HCl, extracted with EtOAc (40 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated. The crude product is purified by prep-HPLC[Column YMC-Actus Triart C18 100×30 mm×5 μm Condition: water (0.05%HCl)-ACN Begin B 30 End B 60 Gradient Time (min) 9.5 100% B Hold Time(min) 2.5 FlowRate (ml/min) 25] to afford title compound (80.0 mg,21.0%) as a yellow solid. LCMS (m/z): 477.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=10.06 (br s, 1H), 8.78 (s, 1H), 8.43 (s,1H), 8.23-8.16 (m, 3H), 7.73 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H),7.44 (d, J=8.0 Hz, 2H), 3.75 (s, 3H), 1.65 (t, J=18.8 Hz, 3H), 1.50-1.43(m, 2H), 1.23-1.15 (m, 2H).

EXAMPLE 13A Methyl1-[4-[6-[5-[[6-(1-fluoro-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add Pd₂(dba)₃ (1.10 g, 1.20 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.04 g, 1.80 mmol) andcesium carbonate (9.80 g, 30.1 mmol) to2-chloro-6-(1-fluoro-1-methyl-ethyl)pyrazine (2.50 g, 12.0 mmol, 84 mass%), methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate(4.19 g, 10.8 mmol, 90 mass %) (Prepared according to Example 1A) in1,4-dioxane (60 mL), then the reaction mixture is stirred at 100° C. for5 h under nitrogen. The reaction mixture is concentrated to afford ablack residue, which is purified by column chromatography on silica geleluting with PE/EtOAc (1:1) to afford the title compound (3.10 g, 50.3%)as yellow solid. LCMS (m/z): 487.2 [M+H]⁺.

EXAMPLE 13B1-[4-[6-[5-[[6-(1-fluoro-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (0.750 g, 17.9 mmol) to methyl1-[4-[6-[5-[[6-(1-fluoro-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(6.10 g, 11.9 mmol) in THF (30 mL) and water (30 mL), then the reactionmixture is stirred at 60° C. for 1 h. The aqueous is acidified by 1N HClto pH=6, then extracted with EtOAc (60 mL×3), the combined organicphases are concentrated to afford crude product. The crude product ispurified by prep-HPLC [column: Phenomenexluna C18 250×50 mm×10condition: 20-45% B (A: water/0.05% HCl, B: CH3CN), flow rate: 25mL/min] and lyophilized to afford title compound (2.7380 g, 37.8%) as ayellow solid. LCMS (m/z): 473.1 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ=8.88 (d, J=2.0 Hz, 1H), 8.67 (dd, J=2.4, 8.8Hz, 1H), 8.36-8.28 (m, 1H), 8.26-8.22 (m, 1H), 8.19 (s, 1H), 8.12-8.05(m, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 3.91-3.85 (m,3H), 1.67-1.62 (m, 2H), 1.40-1.29 (m, 5H), 1.27-1.22 (m, 2H), 1.19 (s,1H)

EXAMPLE 14A Methyl1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-(methoxymethyl)phenyl]cyclopropanecarboxylate 1.Synthesis of Ethyl 2-(4-bromo-3-methyl-phenyl)acetate

Add sulfuric acid (9.2 g, 5 mL) to a mixture of2-(4-bromo-3-methyl-phenyl)acetic acid (5.00 g, 20.7 mmol) in ethanol(50 mL) and the reaction is heated to 80° C. for 3 hours. The mixture iscooled to 20° C. and poured into saturated NaHCO₃ solution (30 mL). Themixture is extracted with EtOAc (30 mL×3). The combined organic layersare washed with brine (30 mL), dried over anhydrous sodium sulfate andconcentrated to afford title compound (5.30 g, 94.4%) as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.48 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 6.98(dd, J=2.0, 8.0 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 2.39 (s,3H), 1.26 (t, J=7.2 Hz, 3H).

2. Synthesis of Ethyl 1-(4-bromo-3-methyl-phenyl)cyclopropanecarboxylate

Add NaH (1.63 g, 40.6 mmol, 60 mass %) to a mixture of ethyl2-(4-bromo-3-methyl-phenyl)acetate (5.00 g, 18.5 mmol) in DMF (50 mL) at20° C. and the mixture is stirred at 50° C. for 1 hour. Then 1,2-dibromoethane (3.68 g, 19.4 mmol) is added and the reaction is stirredat 50° C. for 12 hours. The reaction is quenched with saturated NH₄Clsolution (30 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over anhydroussodium sulfate and concentrated. The residue is purified by flashchromatography eluting with petroleum ether/EtOAc (50:1) to afford thetitle compound (550 mg, 9.99%) as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.46 (d, J=8.4 Hz, 1H), 7.21 (d, J=2.0 Hz,1H), 7.03 (dd, J=2.0, 8.4 Hz, 1H), 4.11 (q, J=7.2 Hz, 2H), 2.39 (s, 3H),1.63-1.56 (m, 2H), 1.22-1.11 (m, 5H).

3. Synthesis of Ethyl1-[4-bromo-3-(bromomethyl)phenyl]cyclopropanecarboxylate

Add NBS (0.369 g, 2.03 mmol) and 2,2′-azobis(2-methylpropionitrile)(31.0 mg, 0.184 mmol) in carbon tetrachloride (10 mL) to a mixture ofethyl 1-(4-bromo-3-methyl-phenyl)cyclopropanecarboxylate (550 mg, 1.84mmol) in carbon tetrachloride (10 mL) and the mixture is heated to 70°C. for 12 hours. The mixture is diluted with water (20 mL) and extractedwith EtOAc (30 mL×3). The combined organic layers are washed with brine(30 mL), dried over anhydrous sodium sulfate and concentrated. Theresidue is purified by flash chromatography eluting with petroleumether/EtOAc (20:1) to afford the title compound (500 mg, 71.1%) ascolorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.51 (d, J=8.4 Hz, 1H), 7.44 (d, J=2.0 Hz,1H), 7.16 (dd, J=2.0, 8.4 Hz, 1H), 4.59 (s, 2H), 4.10 (q, J=7.2 Hz, 2H),1.65-1.60 (m, 2H), 1.21-1.13 (m, 5H).

4. Synthesis of Methyl 1-[4-bromo-3-(methoxymethyl)phenyl]cyclopropaneCarboxylate

Add sodium methoxide (0.0515 g, 0.944 mmol) to a solution of ethyl1-[4-bromo-3-(bromomethyl)phenyl]cyclopropanecarboxylate (300 mg, 0.787mmol) in methanol (5 mL) at 20° C. and the reaction is stirred at 50° C.for 2 hours. The mixture is diluted with water (20 mL) and extractedwith EtOAc (30 mL×3). The combined organic layers are washed with brine(30 mL), dried over anhydrous sodium sulfate, filtered and concentrated.The residue is purified by flash chromatography eluting with petroleumether/EtOAc (20:1) to afford the title compound (200 mg, 80.7%) ascolorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.48 (d, J=8.0 Hz, 1H), 7.44 (d, J=1.6 Hz,1H), 7.14 (dd, J=2.0, 8.0 Hz, 1H), 4.51 (s, 2H), 3.63 (s, 3H), 3.49 (s,3H), 1.65-1.58 (m, 2H), 1.22-1.14 (m, 2H).

5. Synthesis ofN-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropyl-pyrazin-2-amine

Add sodium hydride in oil (1.26 g, 31.5 mmol, 60 mass %) to a suspensionof 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (1.68 g, 6.31 mmol) inDMF (8 mL). The reaction mixture is heated to 50° C. and then2-chloro-6-isopropyl-pyrazine (1.12 g, 6.94 mmol) is added. The reactionmixture is stirred at 50° C. for 1 hour. The reaction mixture is pouredinto saturated ammonium chloride solution (20 mL) and extracted withEtOAc (30 mL*2). The combined organic layers are washed with brine (20mL×2), dried over sodium sulfate and filtered and concentrated to affordthe residue. The residue is purified by column chromatography on silicagel (0-30% EtOAc in PE) to afford title compound (850 mg, 34.3%) as ayellow solid. LCMS (m/z): 373.0 [M+H]⁺.

6. Synthesis of Methyl1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-(methoxymethyl)phenyl]cyclopropanecarboxylate

Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0356g, 0.0476 mmol) to a mixture of methyl1-[4-bromo-3-(methoxymethyl)phenyl]cyclo propanecarboxylate (150 mg,0.476 mmol), bis(pinacolato)diboron (0.128 g, 0.500 mmol) and potassiumacetate (0.142 g, 1.43 mmol) in 1,4-dioxane (5 mL) under nitrogen. Thereaction is heated to 100° C. for 1 hour. The mixture is cooled to 20°C. and thenN-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropyl-pyrazin-2-amine(0.196 g, 0.500 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0356 g,0.0476 mmol), sodium carbonate (0.153 g, 1.43 mmol) and water (0.5 mL)are added under nitrogen. The reaction is heated to 100° C. for 12hours. The mixture is diluted with EtOAc (30 mL) and the solid isfiltered off. The filtrate is diluted with water (30 mL) and extractedwith EtOAc (30 mL×3). The combined organic layers are washed with brine(30 mL), dried over anhydrous sodium sulfate and concentrated. Theresidue is purified by flash chromatography eluting with petroleumether/EtOAc (1:2) to afford title compound (153 mg, 62.7%) as yellowoil. LCMS (m/z): 513.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ=9.38 (s, 1H), 8.54 (d, J=1.6 Hz, 1H), 8.07 (s,1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.74 (dd, J=2.0, 8.0 Hz, 1H), 7.54 (d,J=8.4 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.38 (dd, J=2.0, 8.0 Hz, 1H),7.25 (d, J=7.6 Hz, 1H), 4.31 (s, 2H), 3.87 (s, 3H), 3.66 (s, 3H), 3.37(s, 3H), 3.00-2.92 (m, 1H), 1.68-1.63 (m, 2H), 1.27-1.25 (m, 8H).

EXAMPLE 14B1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-(methoxymethyl)phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (0.0380 g, 0.895 mmol) to a mixture ofmethyl1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-(methoxymethyl)phenyl]cyclopropanecarboxylate(0.170 g, 0.298 mmol, 90 mass %) in THF (3 mL) and water (0.5 mL) andthe mixture is heated to 50° C. for 12 hours. The mixture is adjusted pHto 5-6 with 1.0M HCl solution and the mixture is extracted with EtOAc(30 mL×3). The combined organic layers are washed with brine (30 mL),dried over anhydrous sodium sulfate, filtered and concentrated. Themixture is purified by prep-HPLC (column: YMC-Actus Triart C18 100×30mm×5 μm, Gradient: 32-62% B (A=water/0.05% HCl, B=acetonitrile), Flowrate: 25 mL/min). The desired fractions are lyophilized to afford titlecompound (59.5 mg, 36.9%) as a white solid. LCMS (m/z): 499.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=10.09 (br s, 1H), 8.64 (br s, 1H), 8.36 (brs, 1H), 8.31-8.19 (m, 2H), 7.97-7.80 (m, 2H), 7.50 (br s, 1H), 7.42 (brd, J=7.2 Hz, 1H), 7.30 (d, J 8.0 Hz, 1H), 4.27 (br s, 2H), 3.78 (br s,3H), 3.22 (s, 3H), 2.77-2.63 (m, 1H), 1.56-1.42 (m, 2H), 1.24-1.09 (m,2H), 0.93 (d, J=6.4 Hz, 6H).

EXAMPLE 15A Ethyl1-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate 1.Synthesis of ethyl1-[4-bromo-3-(cyanomethyl)phenyl]cyclopropanecarboxylate

Add trimethylsilyl cyanide (0.0637 g, 0.630 mmol) and tetrabutylammoniumfluoride (1.0 mol/L) in THF (0.63 mL, 0.630 mmol, 1.0 mol/L) to asolution of ethyl1-[4-bromo-3-(bromomethyl)phenyl]cyclopropanecarboxylate (0.200 g, 0.525mmol) (prepared according to Example 14A) in THF (5 mL), and thereaction is stirred at 20° C. for 3 hours. The mixture is diluted withwater (20 mL) and extracted with EtOAc (30 mL×3). The combined organiclayers are washed with brine (30 mL), dried over anhydrous sodiumsulfate and concentrated. The residue is purified by flashchromatography eluting with petroleum ether/EtOAc (20:1) to afford titlecompound (100 mg, 58.7%) as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.54 (d, J=8.4 Hz, 1H), 7.51 (d, J=2.0 Hz,1H), 7.21 (dd, J=2.0, 8.4 Hz, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.84 (s, 2H),1.69-1.61 (m, 2H), 1.24-1.14 (m, 5H).

2. Synthesis of ethyl1-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add Pd(dppf)Cl₂ (0.023 g, 0.031 mmol) potassium acetate (0.0917 g, 0.925mmol) to a mixture of ethyl1-[4-bromo-3-(cyanomethyl)phenyl]cyclopropanecarboxylate (0.100 g, 0.308mmol), bis(pinacolato)diboron (0.083 g, 0.324 mmol) and potassiumacetate (0.0917 g, 0.925 mmol) in 1,4-dioxane (3 mL) under nitrogen. Thereaction is heated to 100° C. for 3 hours. The mixture is cooled to 20°C. and thenN-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropyl-pyrazin-2-amine(0.127 g, 0.324 mmol) (prepared according to Example 14A), Pd(dppf)Cl₂(0.0230 g, 0.0308 mmol), sodium carbonate (0.0990 g, 0.925 mmol) andwater (0.3 mL) are added. The reaction is heated to 100° C. for 3 hours.The solid is filtered off and the filtrate was diluted with water (20mL). The mixture is extracted with EtOAc (30 mL×3). The combined organiclayers ware washed with brine (30 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue is purified by flashchromatography eluting with petroleum ether/EtOAc (1:2) to afford titlecompound (81.0 mg, 50.4%) as a light yellow solid. LCMS (m/z): 522.1[M+H]⁺.

EXAMPLE 15B1-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (0.0079 g, 0.186 mmol) to a mixture ofethyl1-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(90.0 mg, 0.155 mmol, 90 mass %) in THF (2 mL) and water (0.2 mL) andthe mixture is heated to 50° C. for 12 hours. The mixture is adjusted pHto 5-6 with 1.0M HCl solution and the mixture is extracted with EtOAc(30 mL×3). The combined organic layers are washed with brine (30 mL),dried over anhydrous sodium sulfate, filtered and concentrated. Themixture is purified by prep-HPLC (column: YMC-Actus Triart C18 100×30mm×5 μm, Gradient: 35-65% B (A=water/0.05% HCl, B=acetonitrile), Flowrate: 25 mL/min). The desired fractions were lyophilized to afford titlecompound (27.6 mg, 33.2%) as a white solid. LCMS (m/z): 494.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=9.91 (br s, 1H), 8.62 (d, J=1.6 Hz, 1H),8.30 (s, 1H), 8.20-8.12 (m, 2H), 7.92 (s, 1H), 7.88 (d, J=8.4 Hz, 1H),7.53 (s, 1H), 7.43 (dd, J=1.6, 8.0 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 4.00(s, 2H), 3.75 (s, 3H), 2.81-2.70 (m, 1H), 1.57-1.45 (m, 2H), 1.24-1.14(m, 2H), 0.98 (d, J=6.8 Hz, 6H).

EXAMPLE 16A Ethyl1-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate;Hydrochloride 1. Synthesis of Ethyl 2-(4-bromo-3-cyano-phenyl)acetate

Add bromo-(2-ethoxy-2-oxo-ethyl)zinc (2.97 g, 12.7 mmol) (preparedaccording to Example 9A) to a mixture of 2-bromo-5-iodo-benzonitrile(2.60 g, 8.44 mmol), bis(dibenzylideneacetone)palladium (0.121 g, 0.211mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.122 g,0.211 mmol) in THF (20 mL), then the reaction mixture is stirred at 65°C. for 1 h under nitrogen. The reaction mixture is quenched with water(10 mL). The result mixture is extracted with EtOAc (10 mL×3). Thecombined organic phases are washed with water (10 mL), concentrated toafford a black residue, which is purified by column chromatography onsilica gel eluting with PE:EtOAc (20:1) to afford the title compound(1.00 g, 42.0% Yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ=7.65 (d, J=8.4 Hz, 1H), 7.60 (d, J=2.0 Hz,1H), 7.39 (dd, J=2.0, 8.4 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.61 (s, 2H),1.28 (t, J=7.2 Hz, 3H)

2. Synthesis of Ethyl 1-(4-bromo-3-cyano-phenyl)cyclopropanecarboxylate

Add sodium hydride in oil (0.142 g, 3.54 mmol, 60 mass %) to a solutionof ethyl 2-(4-bromo-3-cyano-phenyl)acetate (500 mg, 1.77 mmol) in DMF (5mL), the mixture is stirred at 20° C. for 1 h, then 1,2-dibromoethane(0.333 g, 1.77 mmol) is added to above solution and stirred at 20° C.for 2 h. The reaction mixture is quenched with MeOH (5 mL), diluted withEtOAc (20 mL). The result mixture is washed with water (10 mL×2),concentrated to afford a light yellow residue, which is purified bycolumn chromatography on silica gel eluting with PE:EtOAc (20:1) toafford title compound (260 mg, 47.4%) as a yellow solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68-7.58 (m, 2H), 7.44 (dd, J=2.0, 8.4Hz, 1H), 4.11 (q, J=7.2 Hz, 2H), 1.70-1.65 (m, 2H), 1.21-1.15 (m, 5H)

3. Synthesis of Ethyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-cyano-phenyl]cyclopropanecarboxylate

Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0482g, 0.0646 mmol) to a solution of ethyl1-(4-bromo-3-cyano-phenyl)cyclopropanecarboxylate (200 mg, 0.646 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1,3,2-dioxaborolane(0.182 g, 0.711 mmol) and potassium acetate (0.190 g, 1.94 mmol) in1,4-dioxane (4 mL), then the reaction mixture is stirred at 90° C. for 1h under nitrogen. The reaction mixture is cooled to 20° C., then4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.189 g, 0.711 mmol),sodium carbonate (0.205 g, 1.94 mmol) and water (1 mL) are added toabove solution and stirred at 90° C. for 1 h under nitrogen. Thereaction mixture is concentrated to afford a black residue, which ispurified by column chromatography on silica gel eluting with EtOAc toafford title compound (130 mg, 46.7%) as a yellow oil. LCMS (m/z): 388.1[M+H]⁺.

4. Synthesis of Ethyl1-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate;Hydrochloride

Add tris(dibenzylideneacetone)dipalladium (0.0277 g, 0.0302 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0262 g, 0.0453 mmol)to a suspensions of ethyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-cyano-phenyl]cyclopropanecarboxylate(130 mg, 0.302 mmol), 2-chloro-6-isopropyl-pyrazine (0.0585 g, 0.362mmol) and cesium carbonate (0.295 g, 0.906 mmol) in 1,4-dioxane (5 mL),then the reaction mixture is stirred at 100° C. for 3 h under nitrogen.The reaction mixture is concentrated to afford a black residue, which ispurified by column chromatography on silica gel eluting with EtOAc toafford crude product, which is purified by prep-HPLC [column:YMC-ActusTriart C18 150×30 mm×5 μm, condition: 45-75% B (A: water/0.05%HCl, B: CH3CN), flow rate: 25 mL/min] to afford title compound (60.0 mg,35.1%) as a yellow solid. LCMS (m/z): 508.2 [M+H]⁺.

EXAMPLE 16B1-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (4.4 mg, 0.106 mmol) to a solution ofethyl1-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate;hydrochloride (60.0 mg, 0.106 mmol) in methanol (1 mL) and water (1 mL),then the reaction mixture is stirred at 60° C. for 1 h. The reactionmixture is diluted with water (10 mL), acidified by 1N HCl to pH=4. Theprecipitate is filtered and dried over vacuo to afford the titlecompound (29.5 mg, 96.9 mass %, 52.3%) as a white solid. LCMS (m/z):480.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ=8.65 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.92(d, J=8.0 Hz, 1H), 7.85 (s, 2H), 7.74 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 3.80 (s, 3H), 2.89-2.80 (m, 1H),1.67-1.60 (m, 2H), 1.28-1.20 (m, 2H), 1.10 (d, J=7.2 Hz, 6H)

EXAMPLE 171-[4-[4-[5-[(6-isobutylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicAcid 1. Synthesis of Methyl 1-(4-bromophenyl)cyclopropanecarboxylate

Add 1-(4-bromophenyl)cyclopropanecarboxylic acid (10.0 g, 41.5 mmol) inDMF (50.0 mL, 646 mmol) to potassium carbonate (11.5 g., 83.0 mmol) andiodomethane (11.7 g, 83.0 mmol). Then the reaction mixture is stirred at20° C. for 0.5 h. the reaction mixture is added with water (50 mL) andthe result mixture is extracted with EtOAc (50 mL×3), then the combinedorganic phases is washed with water (30 mL×2), dried over anhydroussodium sulfate, filtered and concentrated to give the title compound(10.0 g, 94.5%) as a colorless oil. LCMS (m/z): 254.8/256.8 [M+H,Br⁷⁹/Br⁸¹]⁺.

2. Synthesis of Methyl1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate

Add methyl 1-(4-bromophenyl)cyclopropanecarboxylate (10.0 g, 39.2 mmol)and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(10.5 g., 41.2 mmol) in dioxane (50.0 mL) to potassium acetate (18.9 g,137 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(2.9 g, 3.92 mmol). Then the reaction mixture is stirred at 100° C. for2 h under N₂. To the reaction mixture is added water (50 mL) and EtOAc(100 mL). The solution is separated and the aqueous is extracted withEtOAc (50 mL×3). The combined organic phases are washed with brine (50mL×2), water (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated to give the title compound (10.0 g, 84.4%) as a whitesolid. LCMS (m/z): 303.1 [M+H]⁺.

3. Synthesis of Methyl1-[4-(4-bromophenyl)phenyl]cyclopropanecarboxylate

Add 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate (10.0 g, 33.1 mmol), 1-bromo-4-iodo-benzene (10.5 g,34.7 mmol) in dioxane (50.0 mL) and water (10.0 mL) to potassiumcarbonate (9.1 g., 66.2 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (2.4 g, 3.31mmol). The reaction mixture is stirred at 100° C. for 2 h under N₂. Thereaction mixture is concentrated to give a black solid, which waspurified by column chromatography (PE:EtOAc=10:1) to give the titlecompound (10.0 g, 91.2%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=7.56-7.40 (m, 8H), 3.65 (s, 3H), 1.64 (m, 2H),1.22 (m, 2H).

4. Synthesis of Methyl1-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phenyl]cyclopropanecarboxylate

Add methyl 1-[4-(4-bromophenyl)phenyl]cyclopropanecarboxylate (10.0 g,30.2 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(8.1 g, 31.7 mmol,) in 1,4-dioxane (50.0 mL) to potassium acetate (14.6g, 106 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(2.2 g, 3.02 mmol). Then the reaction mixture is stirred at 100° C. for2 h under N₂. The reaction mixture is concentrated to give a blacksolid. The black solid is purified by column chromatography(PE:EtOAc=10:1) to give the title compound (8.00 g, 70.0%) as a lightyellow solid.

¹H NMR (400 MHz, CDCl₃) δ=7.87 (m, 2H), 7.61-7.57 (m, 4H), 7.41 (m, 2H),3.65 (s, 3H), 1.64 (m, 2H), 1.22 (m, 2H).

5. Synthesis of Methyl1-[4-[4-(5-amino-1-methyl-pyrazol-4-yl)phenyl]phenyl]cyclopropanecarboxylate

Add 1-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phenyl]cyclopropanecarboxylate (2.00 g, 5.29 mmol),4-bromo-2-methyl-pyrazol-3-amine (1.1 g, 6.34 mmol),tetrakis(triphenylphosphine)palladium (0.60 g, 0.529 mmol) in ethanol(4.00 mL), toluene (20.0 mL) and water (3.00 mL) to sodium carbonate(2.3 g, 21.1 mmol). The mixture is stirred at 110° C. for 4 h under N₂.The reaction mixture is concentrated to give a yellow residue. Theresidue is purified by column chromatography (DCM:MeOH=10:1) to give thetitle compound (1.12 g, 61.0%) as a yellow solid. LCMS (m/z): 347.9[M+H]⁺.

6. Synthesis of1-[4-[4-[5-[(6-chloropyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicAcid

Add sodium hydride (60 mass %) in oil (0.131 g, 3.28 mmol, 60 mass %) tothe solution of methyl1-[4-[4-(5-amino-1-methyl-pyrazol-4-yl)phenyl]phenyl]cyclopropanecarboxylate(300 mg, 0.820 mmol) in DMF (3 mL). The reaction mixture is heated to50° C. and then 2, 6-dichloropyrazine (0.123 g, 0.820 mmol) is added.The reaction mixture is stirred at 50° C. for 2 hours. The reactionmixture is poured into ammonium chloride solution (50 ml) and extractedwith EtOAc (50 mL×2). The combined organic layers are washed with brine(40 mL×3), dried over sodium sulfate, filtered and concentrated toafford the crude product. The crude product is purified by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 μm, Gradient: 36-66% B(A=water/0.05% HCl, B=acetontrile), Flow rate: 25 mL/min) to afford thetitle product (75.0 mg, 20.8%) as a yellow solid. LCMS (m/z) 446.0[M+H]⁺.

7. Synthesis of1-[4-[4-[1-methyl-5-[[6-(2-methylprop-1-enyl)pyrazin-2-yl]amino]pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicAcid

Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.0127 g,0.0170 mmol) to a solution of4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (0.0329g, 0.179 mmol), sodium carbonate (0.0361 g, 0.341 mmol) and1-[4-[4-[5-[(6-chloropyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicacid (75.0 mg, 0.170 mmol) in 1,4-dioxane (6 mL) and water (1 mL) underN₂. Then the reaction mixture is stirred at 100° C. for 2 h under N₂.The mixture is diluted with water (30 mL) and extracted with EtOAc (40mL×3). The combined organic layers were washed with brine (40 mL), driedover anhydrous Na₂SO₄, filtered and evaporated to afford the titleproduct (63.0 mg 79.4%) as a yellow solid. LCMS: (m/z) 466.2 [M+H]⁺.

8. Synthesis of1-[4-[4-[5-[(6-isobutylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicAcid

Add palladium on activated carbon (10.0 mg, 10 mass %) to a solution of1-[4-[4-[1-methyl-5-[[6-(2-methylprop-1-enyl)pyrazin-2-yl]amino]pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylic acid (70.0 mg, 0.135mmol, 90 mass %) in methanol (5 mL). Then the reaction mixture isstirred under molecular hydrogen (15 psi, balloon) at 25° C. for 1 h.The mixture is filtered and the filtrate is concentrated to afford thecrude product. The crude product is purified by prep-HPLC [Column:YMC-Actus Triart C18 150×30 5 μm; Condition: 43-73% B (A=0.05% HCl,B=acetonitrile); FlowRate: 25 mL/min] to afford the title product (22.0mg, 34.8%) as a yellow solid.

LCMS: (m/z) 468.4 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d6) δ=9.17 (s, 1H), 7.92-7.85 (m, 2H), 7.78 (s,1H), 7.58-7.51 (m, 6H), 7.40-7.32 (m, 2H), 3.65 (s, 3H), 2.34 (d, J=6.8Hz, 2H), 1.87-1.74 (m, 1H), 1.50-1.42 (m, 2H), 1.18-1.11 (m, 2H), 0.75(d, J=6.8 Hz, 6H).

EXAMPLE 18A Methyl1-[4-[2-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrimidin-5-yl]phenyl]cyclopropanecarboxylate 1.Synthesis of (E)-2-(5-bromopyrimidin-2-yl)-3-ethoxy-prop-2-enenitrile

Add acetic anhydride (2.50 g, 23.7 mmol) to a solution of2-(5-bromopyrimidin-2-yl)acetonitrile (950 mg, 4.75 mmol) and triethylorthoformate (3 mL, 17.7 mmol), the reaction mixture is stirred at 120°C. for 5 h. The reaction mixture is concentrated to afford titlecompound (0.96 g, 79.6%) as brown crude. LCMS (m/z): 255.9 [M+H]⁺.

2. Synthesis of 4-(5-bromopyrimidin-2-yl)-2-methyl-pyrazol-3-amine

Add methylhydrazine (2.18 g, 18.9 mmol, 40 mass %) to a solution of(E)-2-(5-bromopyrimidin-2-yl)-3-ethoxy-prop-2-enenitrile (0.96 g, 3.78mmol) is dissolved in ethanol (3 mL). The reaction mixture is heated to100° C. for 2 hours. The reaction mixture is concentrated, and purifiedby flash chromatography eluting with petroleum ether:EtOAc (3:1) toafford title compound (0.7 g, 72.9%) as a brown crude.

¹H NMR (DMSO-d6, 400 MHz) δ=8.74 (s, 2H), 8.02 (s, 1H), 7.70 (s, 1H),6.50 (br s, 2H), 4.87-4.72 (m, 1H), 4.79 (br s, 1H), 3.57 (s, 3H), 2.90(s, 2H).

3. Synthesis ofN-[4-(5-bromopyrimidin-2-yl)-2-methyl-pyrazol-3-yl]-6-isopropyl-pyrazin-2-amine

Add sodium hydride in oil (0.165 g, 4.13 mmol, 60 mass %) to thesuspension of 4-(5-bromopyrimidin-2-yl)-2-methyl-pyrazol-3-amine (210mg, 0.826 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture isheated to 50° C. and then 2-chloro-6-isopropyl-pyrazine (0.140 g, 0.909mmol) is added. The reaction mixture is stirred at 50° C. for 3 hours.The reaction mixture is poured into ammonium chloride solution (50 ml)and extracted with EtOAc (50 mL×2). The combined organic layers arewashed with brine (20 mL), dried over sodium sulfate and concentrated toafford the crude product. The crude product is purified by flashchromatography eluting with petroleum ether:EtOAc (1:3) to afford titlecompound (140 mg, 45.3%) as a yellow solid. LCMS (m/z): 374.0 [M+H]⁺.

4. Synthesis of methyl1-[4-[2-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrimidin-5-yl]phenyl]cyclopropanecarboxylate

Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0140g, 0.0187 mmol) to a suspensions of methyl1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate(0.125 g, 0.393 mmol), sodium carbonate (0.0793 g, 0.748 mmol) andN-[4-(5-bromopyrimidin-2-yl)-2-methyl-pyrazol-3-yl]-6-isopropyl-pyrazin-2-amine(200 mg, 0.374 mmol, 70 mass %) in 1,4-dioxane (4 mL) and water (1 mL)under N₂. Then the reaction mixture is stirred at 100° C. for 3 h underN₂. The reaction mixture is concentrated to give a black solid. Themixture is diluted with water (20 mL) and extracted with EA (30 mL×3).The combined organic layers are washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and evaporated to afford the crude product.The crude product is purified by flash chromatography eluting withpetroleum ether:EtOAc (1:2) to afford title compound (90 mg, 51.2%) as ayellow solid, LCMS (m/z): 470.2 [M+H]⁺.

EXAMPLE 18B1-[4-[2-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrimidin-5-yl]phenyl]cyclopropanecarboxylicacid

Add lithium hydroxide hydrate (0.0205 g, 0.479 mmol) to a solution ofmethyl1-[4[2-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrimidin-5-yl]phenyl]cyclopropanecarboxylate(90 mg, 0.192 mmol,) in THF (4 mL) and water (2 mL). The reactionmixture is stirred at 50° C. for 12 hours. The mixture is adjusted topH=5-6 with 1 N HCl, extracted with EtOAc (40 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated. The crude product is purified by prep-HPLC[Column: YMC-Actus Triart C18 150×30, 5 μm; Condition: 36-66% B (A=0.05%HCl, B=acetonitrile); FlowRate: 25 mL/min] to afford the title compound(44.3 mg, 50.7% Yield) as a white solid, LCMS (m/z): 456.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=9.43 (s, 1H), 8.92 (s, 2H), 8.12 (s, 1H),8.09 (s, 1H), 7.87 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz,2H), 3.71 (s, 3H), 2.79-2.71 (m, 1H), 1.49-1.43 (m, 2H), 1.18-1.13 (m,2H), 0.98 (d, J=6.8 Hz, 6H).

EXAMPLE 19A Methyl1-[4-[5-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrazin-2-yl]phenyl]cyclopropanecarboxylate 1.Synthesis of methyl1-[4-(5-chloropyrazin-2-yl)phenyl]cyclopropanecarboxylate

Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.445g, 0.596 mmol) to the suspensions of methyl1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate (2.00 g, 5.4 mmol,), sodium carbonate (1.26 g, 11.9mmol) and 2,5-dichloropyrazine (8.93 mmol) in 1,4-dioxane (20 mL) andwater (4 mL) under N₂. Then the reaction mixture is stirred at 100° C.for 3 h under N₂. The reaction mixture is concentrated to give a blacksolid. The mixture is diluted with water (20 mL) and extracted withEtOAc (30 mL×3). The combined organic layers are washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and evaporated to afford thecrude product. The crude product is purified by flash chromatographyeluting with petroleum ether:EtOAc (1:2) to afford title compound (1.0 g57.6%) as a yellow solid, LCMS (m/z): 288.9 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ=8.80 (d, J=1.2 Hz, 1H), 8.65 (d, J=1.2 Hz,1H), 7.96 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 3.67 (s, 3H),1.72-1.66 (m, 2H), 1.28-1.23 (m, 2H).

2. Synthesis of methyl1-[4-(5-tributylstannylpyrazin-2-yl)phenyl]cyclopropanecarboxylate

Add tetrakis(triphenylphosphine)palladium(0) (0.108 g, 0.0935 mmol) andtricyclohexylphosphine (0.0535 g, 0.187 mmol) to a solution of methyl1-[4-(5-chloropyrazin-2-yl)phenyl]cyclopropanecarboxylate (540 mg, 1.87mmol), hexabutylditin (1.71 g, 2.81 mmol) and lithium chloride (0.481 g,11.2 mmol) in 1,4-dioxane (3 mL) under N₂. The mixture is stirred at100° C. for 12 hours. The solid is filtered off. The mixture is dilutedwith sat. KF (20 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over anhydrousNa₂SO₄, filtered and evaporated to afford the crude product. The crudeproduct is purified by flash chromatography eluting with petroleumether:EtOAc (3:1) to afford title compound (288 mg, 28.3%) as a brownsolid, LCMS (m/z): 545.1 [M+H]⁺.

3. Synthesis of Methyl1-[4-[5-[5-(tert-butoxycarbonylamino)-1-methyl-pyrazol-4-yl]pyrazin-2-yl]phenyl]cyclopropanecarboxylate

Add bis(tri-tert-butylphosphine)palladium(0) (0.0276 g, 0.0530 mmol) tothe suspensions of methyl1-[4-(5-tributylstannylpyrazin-2-yl)phenyl]cyclopropanecarboxylate (288mg, 0.530 mmol) and tert-butyl N-(4-iodo-2-methyl-pyrazol-3-yl)carbamate(0.256 g, 0.795 mmol) in 1,4-dioxane (4 mL) under N₂. The mixture isstirred at 80° C. for 16 hours. The solid is filtered off. The mixtureis diluted with sat. KF (20 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers are washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and evaporated to afford the crude product.The crude product is purified by flash chromatography eluting withpetroleum ether:EtOAc (1:3) to afford title compound (67.0 mg, 28.3%) asa brown solid, LCMS (m/z): 450.2 [M+H]⁺.

4. Synthesis of Methyl1-[4-[5-(5-amino-1-methyl-pyrazol-4-yl)pyrazin-2-yl]phenyl]cyclopropanecarboxylate

Add trifluoroacetic acid (1 mL) to a solution of methyl1-[4-[5-[5-(tert-butoxycarbonylamino)-1-methyl-pyrazol-4-yl]pyrazin-2-yl]phenyl]cyclopropanecarboxylate(67.0 mg, 0.150 mmol) in dichloromethane (3 mL. The solution is stirredat 25° C. for 2 hours. The reaction is concentrated under reducedpressure. The residue is added into sat. Na₂CO₃ solution (10 mL) andextracted with CH₂Cl₂ (15 mL×3). The combined organic layers are washedwith brine (30 mL), dried over sodium sulfate, filtered, concentrated toafford title compound (32.0 mg, 60.0%) as yellow solid. LCMS (m/z):350.1 [M+H]⁺.

5. Synthesis of Methyl1-[4-[5-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrazin-2-yl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium(0) (0.00730 g, 0.00773 mmol)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.00691 g, 0.0116mmol) to the suspensions of methyl1-[4-[5-(5-amino-1-methyl-pyrazol-4-yl)pyrazin-2-yl]phenyl]cyclopropanecarboxylate(27.0 mg, 0.0773 mmol), 2-chloro-6-isopropyl-pyrazine (0.0136 g, 0.0850mmol) and cesium carbonate (0.0504 g, 0.155 mmol) in 1,4-dioxane (4 mL)under N₂. The mixture is stirred at 100° C. for 2 hours. The solid isfiltered off. The mixture is diluted with water (20 mL) and extractedwith EtOAc (30 mL×3). The combined organic layers are washed with brine(30 mL), dried over anhydrous Na₂SO₄, filtered and evaporated to affordthe crude product. The crude product is purified by flash chromatographyeluting with petroleum ether:EtOAc (1:3) to afford title compound (16.0mg, 44.1%) as a brown solid, LCMS (m/z): 470.2 [M+H]⁺.

EXAMPLE 19B1-[4-[5-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrazin-2-yl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add lithium hydroxide hydrate (0.00433 g, 0.102 mmol) to a mixture ofmethyl1-[4-[5-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrazin-2-yl]phenyl]cyclopropanecarboxylate(16 mg, 0.0341 mmol, 80 mass %) in THF (1 mL) and water (0.5 mL) isstirred at 60° C. for 4 hours. The mixture is adjusted pH to 5-6 with1.0M HCl solution and the mixture is extracted with EtOAc (30 mL×3). Thecombined organic layers are washed with brine (30 mL), dried overanhydrous sodium sulfate and concentrated to afford the crude. The crudeproduct is purified by prep-HPLC [Column: YMC-Actus Triart C18 150×30, 5μm; Condition: 36-66% B (A=0.05% HCl, B=acetonitrile); FlowRate: 25mL/min] to afford title compound (6.3 mg, 37%) as an off-white solid.LCMS (m/z): 456.0 [M+H]⁺.

¹H NMR (METHANOL-d4, 400 MHz) δ=8.93 (s, 1H), 8.85 (s, 1H), 8.59-7.70(m, 5H), 7.51 (d, J=8.4 Hz, 2H), 3.86 (s, 3H), 3.00-2.92 (m, 1H),1.65-1.61 (m, 2H), 1.28-1.21 (m, 2H), 1.10 (d, J=6.8 Hz, 6H).

EXAMPLE 20A Methyl1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate(240 mg, 0.654 mmol) (prepared according to Example 1A),2-chloro-6-isopropoxy-pyrazine (138 mg, 0.720 mmol) and cesium carbonate(427 mg, 1.31 mmol) in O₂-free 1,4-dioxane (10 mL) totris(dibenzylideneacetone)dipalladium (61.8 mg, 0.0654 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58.6 mg, 0.0982 mmol)at 25° C. The mixture is then stirred at 100° C. for 6 hours. Themixture is filtered through a pad of silica gel (200-300 mush) and thefiltrate is concentrated. The residue is purified by flash chromatographeluting with petroleum ether:EtOAc=1:1 to afford the title compound (200mg, 59.3%) as brown oil. LCMS (m/z): 485.2 [M+H]⁺.

EXAMPLE 20B1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add methyl1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(200 mg, 0.388 mmol) in THF (4 mL) and water (2 mL) to lithium hydroxidemonohydrate (48.8 mg, 1.16 mmol). The resulting mixture is stirred for12 hours at 25° C. The mixture is concentrated and diluted with water (5mL). The mixture is acidified with HCl (1M) to pH=˜6. The mixture isextracted with DCM (5 mL×5). The combined organic phases are washed withbrine (10 mL), concentrated. The residue is purified by prep-HPLC[column: DYA-5 C18 150×25 mm×5 μm, condition: 18-48% B (A: water/0.05%HCl, B: acetonitrile), flow rate: 25 mL/min] to afford the titlecompound1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid (48.0 mg, 24.4%) as yellow solid. LCMS (m/z): 471.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.45(d, J=8.4 Hz, 1H), 8.31 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.83 (s, 1H),7.71 (d, J=8.0 Hz, 2H), 7.54 (s, 1H), 7.47 (d, J=8.0 Hz, 2H), 4.73-4.59(m, 1H), 3.76 (s, 3H), 1.54-1.45 (m, 2H), 1.23-1.14 (m, 2H), 1.05 (d,J=6.0 Hz, 6H).

EXAMPLE 21A Methyl1-[4-[6-[1-methyl-5-[[6-(trifluoromethyl)pyrazin-2-yl]amino]pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add methyl1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate(240 mg, 0.654 mmol) (prepared according to Example 1A),2-chloro-6-(trifluoromethyl)pyrazine (131 mg, 0.720 mmol) and cesiumcarbonate (427 mg, 1.31 mmol) in 02-free 1,4-dioxane (10 mL) totris(dibenzylideneacetone)dipalladium(0) (61.8 mg, 0.0654 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58.6 mg, 0.0982 mmol)at 25° C. The mixture is then stirred at 100° C. for 6 hr. The mixtureis filtered through a pad of silica gel (200-300 mush) and the filtrateis concentrated. The residue is purified by flash chromatograph elutingwith petroleum ether:EtOAc (1:1) to afford the title compound (280 mg,65.8%) as light yellow oil. LCMS (m/z): 495.2 [M+H]⁺.

EXAMPLE 21B1-[4-[6-[1-methyl-5-[[6-(trifluoromethyl)pyrazin-2-yl]amino]pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid

Add methyl1-[4-[6-[1-methyl-5-[[6-(trifluoromethyl)pyrazin-2-yl]amino]pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate(280 mg, 0.430 mmol) in THF (4 mL) and water (2 mL) to lithium hydroxidemonohydrate (54.2 mg, 1.29 mmol). The resulting mixture is stirred for12 hours at 25° C. The mixture is concentrated and diluted with water (5mL). The mixture is acidified with HCl (1M) to pH=4-6. The mixture isextracted with DCM (5 mL×5). The combined organic phases are washed withbrine (10 mL), concentrated, lyophilized to afford the title compound(92.0 mg, 42.1%) as yellow solid. LCMS (m/z): 481.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ 10.13 (br s, 1H), 8.70 (d, J=2.0 Hz, 1H),8.49 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 8.04-7.93 (m, 1H), 7.70-7.58(m, 3H), 7.41 (d, J=8.0 Hz, 2H), 3.71 (s, 3H), 1.51-1.43 (m, 2H),1.20-1.13 (m, 2H).

EXAMPLE 221-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-methyl-phenyl]cyclopropanecarboxylicAcid; Hydrochloride 1. Synthesis of1-(4-bromo-3-methyl-phenyl)cyclopropanecarbonitrile

Add sodium hydride in paraffin oil (952 mg, 23.8 mmol, 60 mass %) to asolution of 2-(4-bromo-3-methyl-phenyl)acetonitrile (1.00 g, 4.76 mmol)in THF (5 mL) at 0° C. under N₂. The mixture is stirred at 20° C. for 1hour. 1, 2-dibromoethane (1.07 g, 5.71 mmol) is added to the abovemixture. The mixture is stirred at 20° C. for 3 hours. The mixture isdiluted with saturated NH₄Cl (30 mL) and extracted with EtOAc (40 mL×3).The combined organic layers are washed with brine (40 mL), dried overanhydrous Na₂SO₄, filtered and evaporated to afford the crude product.The crude product is purified by column chromatography on silica gel(0-8%, EtOAc in PE) to afford the title compound (576 mg, 51.2%) as ayellow solid.

¹H NMR (400 MHz, CDCl₃) δ=7.50 (d, J=8.0 Hz, 1H), 7.20 (d, J=2.0 Hz,1H), 6.94 (dd, J=8.0, 2.0 Hz, 1H), 2.41 (s, 3H), 1.79-1.66 (m, 2H),1.44-1.33 (m, 2H)

2. Synthesis of1-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarbonitrile

Add Pd(dppf)Cl₂ (182 mg, 0.244 mmol) to a mixture of1-(4-bromo-3-methyl-phenyl)cyclopropanecarbonitrile (576 mg, 2.44 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(650 mg, 2.56 mmol) and KOAc (479 mg, 4.88 mmol) in 1,4-dioxane (6 mL)under N₂. The mixture is stirred at 100° C. for 3 hours. The solid isfiltered off. The mixture is diluted with water (20 mL) and extractedwith EtOAc (40 mL×3). The combined organic layers are washed with brine(40 mL), dried over anhydrous Na₂SO₄, filtered and evaporated to affordthe crude product. The crude product is purified by columnchromatography on silica gel (0-8%, EtOAc in PE) to afford title product(700 mg, 70 mass %, 71%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ=7.74 (d, J=8.0 Hz, 1H), 7.11 (d, J=1.2 Hz,1H), 7.04 (dd, J=8.0, 1.2 Hz, 1H), 2.54 (s, 3H), 1.78-1.68 (m, 2H),1.45-1.39 (m, 2H), 1.34 (s, 12H)

3. Synthesis of1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-methyl-phenyl]cyclopropanecarbonitrile

Add Pd(dppf)Cl₂ (27.7 mg, 0.0371 mmol) to a mixture of1-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarbonitrile(300 mg, 0.742 mmol, 70 mass %),4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (229 mg, 0.816 mmol, 90mass %) and Na₂CO₃ (196 mg, 1.85 mmol) in water (1 mL) and 1,4-dioxane(4 mL) under N₂. The mixture is stirred at 100° C. for 5 hours. Thesolid is filtered off. The filtrate is diluted with water (20 mL) andextracted with EtOAc (40 mL×3). The combined organic layers are washedwith brine (40 mL), dried over anhydrous Na₂SO₄, filtered and evaporatedto afford the crude product. The crude product is purified by columnchromatography on silica gel (0-70%, EtOAc in PE) to afford titleproduct (200 mg, 85.2%) as a yellow solid. LCMS (m/z): 330.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ=8.42 (d, J=1.6 Hz, 1H), 7.73 (s, 1H), 7.56(dd, J=8.4, 2.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.27-7.25 (m, 1H), 7.22(d, J=7.6 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 5.72-5.46 (m, 2H), 3.72(s, 3H), 2.32 (s, 3H), 1.85-1.69 (m, 2H), 1.50-1.42 (m, 2H).

4. Synthesis of1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-methyl-phenyl]cyclopropanecarboxylicAcid

Add NaOH (300 mg) in water (3 mL) to a solution of1-[4-[6-[5-amino-I-methyl-pyrazol-4-yl)-3-pyridyl]-3-methyl-phenyl]cyclopropanecarbonitrile(200 mg, 0.631 mmol) in ethanol (3 mL). The mixture is stirred at 80° C.for 3 hours. The mixture is neutralized with HCl (1M, 20 mL) andextracted with CH₂Cl₂ (40 mL×3). The combined organic layers are washedwith brine (40 mL), dried over anhydrous Na₂SO₄, filtered and evaporatedto afford title product (140 mg, 63.6%) as a yellow solid. LMCS (m/z):349.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆,) δ=12.34 (br s, 1H), 8.41 (d, J=1.6 Hz, 1H),7.80 (s, 1H), 7.68 (dd, J=8.4, 2.4 Hz, 1H), 7.63-7.55 (m, 1H), 7.36-7.14(m, 3H), 6.49 (s, 2H), 3.59 (s, 3H), 2.27 (s, 3H), 1.52-1.41 (m, 2H),1.21-1.12 (m, 2H)

5. Synthesis of1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-methyl-phenyl]cyclopropanecarboxylicAcid; Hydrochloride

Add sodium hydride in oil (92.0 mg, 2.3 mmol, 60 mass %) to a solutionof1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-methyl-phenyl]cyclopropanecarboxylicacid (200 mg, 0.46 mmol, 80 mass %) in DMF (4 mL) at 0° C. under N₂ andthen the mixture is stirred at 50° C. for 10 min. A solution of2-chloro-6-isopropyl-pyrazine (110 mg, 0.51 mmol, 70 mass %) in DMF (1mL) is added to the above mixture. The mixture is stirred at 50° C. for3 hours. The mixture is neutralized with HCl (1M) and extracted withCH₂Cl₂ (30 mL*3). The combined organic layers are washed with brine (30mL), dried over anhydrous Na₂SO₄, filtered and evaporated to afford thecrude product. The crude product is purified by pre-HPLC [column:YMC-Actus Triart C18 150*30, 5 μm, condition: 25-55% B, A: water (0.05%HCl), B: ACN, flow rate: 25 mL/min] to afford title product (24.8 mg,99.1 mass %, 28.6%) as a yellow solid. LCMS (m/z): 469.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=9.78 (br s, 1H), 8.59 (br s, 1H), 8.28-8.18(m, 1H), 8.17-8.00 (m, 2H), 7.90 (s, 1H), 7.84-7.69 (m, 1H), 7.31 (s,1H), 7.26 (d, J=8.0 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 3.75 (s, 3H),2.79-2.68 (m, 1H), 2.23 (s, 3H), 1.52-1.40 (m, 2H), 1.19-1.11 (m, 2H),0.95 (d, J=6.8 Hz, 6H).

EXAMPLE 23 Ammonia;1-[5-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-pyridyl]cyclopropanecarboxylicAcid 1. Synthesis of1-[5-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-2-pyridyl]cyclopropanecarbonitrile

Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.251 g,0.336 mmol) to a solution of4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.90 g, 3.53 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(0.915 g, 3.53 mmol), 1-(5-bromo-2-pyridyl)cyclopropanecarbonitrile(0.75 g, 3.36 mmol) and potassium acetate (0.842 g, 8.41 mmol) in1,4-dioxane (8 mL) and water (1 mL) under N₂. Then the reaction mixtureis stirred at 100° C. for 12 h under N₂. The reaction mixture isconcentrated to give a black solid, which is purified by flashchromatography eluting with EtOAc:PE (3:1) to give title compound (150mg, 13.4%) as a brown solid.

LCMS (m/z): 317.0 [M+H]⁺.

2. Synthesis of1-[5-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-2-pyridyl]cyclopropanecarboxylicAcid

Add sodium hydroxide (32.0 mass %) in water (3 mL) to a solution of1-[5-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-2-pyridyl]cyclopropanecarbonitrile(150 mg, 0.450 mmol) in ethanol (3.00 mL) and water (1.00 mL). Thereaction mixture is stirred at 80° C. for 12 hours. The mixture isadjusted to pH=6-7 with 1 N HCl and extracted with CH₂Cl₂ (30 mL×3). Thecombined organic layers are dried over anhydrous sodium sulfate andconcentrated to afford title compound (68.0 mg, 40.6%) as a brown solid,LCMS (m/z): 336.0 [M+H]⁺.

3. Synthesis of Ammonia1-[5-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-pyridyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (0.0173 g, 0.0183 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0164 g, 0.0274 mmol)to a solution of1-[5-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-2-pyridyl]cyclopropanecarboxylicacid; hydrochloride (68.0 mg, 0.183 mmol), 2-chloro-6-isopropyl-pyrazine(0.032 g, 0.201 mmol) and cesium carbonate (0.179 g, 0.549 mmol) in1,4-dioxane (4 mL) under N₂. The mixture is stirred at 100° C. for 2hours. The solid is filtered off. The mixture is acidified to pH=5-6,filtered and evaporated to afford the crude. It is purified by prep-HPLC[Column: YMC-Actus Triart C18 150×30, 5 μm; Condition: 36-66% B (A=0.05%HCl, B=acetonitrile); FlowRate: 25 mL/min] to afford the product (90mg). Then it is purified by prep-HPLC [Column: YMC-Actus Triart C18150×30, 5 μm; Condition: 36-66% B (A=0.05% NH₃.H₂O, B=acetonitrile);FlowRate: 25 mL/min] to afford title compound (30 mg, 34.9%) as a whitesolid, LCMS (m/z): 456.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ=8.82-8.68 (m, 2H), 8.11-7.99 (m, 4H), 7.87 (s,1H), 7.68 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 3.82 (s, 3H),2.91-2.85 (m, 1H), 1.78-1.67 (m, 2H), 1.44-1.41 (m, 2H), 1.12 (d, J=6.8Hz, 6H).

EXAMPLE 241-[6-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-pyridyl]cyclopropanecarboxylicAcid; Dihydrochloride 1. Synthesis of1-(6-chloro-3-pyridyl)cyclopropanecarbonitrile

Add sodium hydride (3.89 g, 97.3 mmol, 60 mass %) to the solution of2-(6-chloro-3-pyridyl)acetonitrile (5.00 g, 32.4 mmol) intetrahydrofuran (50 mL) at 0° C. The reaction is stirred at 20° C. for20 min and then 1-bromo-2-chloro-ethane (5.64 g, 38.9 mmol) is added.The reaction is stirred at 10° C. for 3 hours. The mixture is added intoaq. NaCl (20 mL). The mixture is extracted with EtOAc (20 mL×3). Thecombined organic layers are washed with brine (10 mL), dried overanhydrous sodium sulfate and concentrated to afford (4.20 g, 72.5%) as ayellow solid, LCMS (m/z): 178.9 [M+H]⁺.

2. Synthesis of 1-(6-tributylstannyl-3-pyridyl)cyclopropanecarbonitrile

Add 1-(6-chloro-3-pyridyl)cyclopropanecarbonitrile (1.2.0 g, 6.72 mmol),lithium chloride (1.73 g, 40.3 mmol) and hexabutylditin (6.15 g, 10.1mmol) in 1, 4-dioxane (20 mL) to tris(dibenzylideneacetone)dipalladium(0.317 g, 0.336 mmol) and tricyclohexylphosphine (0.192 g, 0.672 mmol)under N₂. The mixture is stirred at 100° C. for 12 hours. The solid isfiltered off. The mixture is diluted with sat. KF (20 mL) and extractedwith EtOAc (30 mL×3). The combined organic layers are washed with brine(30 mL), dried over anhydrous Na₂SO₄, filtered and evaporated to affordthe crude product. The crude product is purified by flash chromatographyeluting with petroleum ether:EtOAc (3:1) to afford title compound (9.6g, 33.0%) as a brown solid, LCMS (m/z): 435.1 [M+H]⁺.

3. Synthesis of1-[6-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-pyridyl]cyclopropanecarbonitrile;Hydrochloride

Add 1-(6-tributylstannyl-3-pyridyl)cyclopropanecarbonitrile (0.240 g,0.560 mmol), lithium chloride (0.0685 g, 1.60 mmol) and4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (135 mg, 0.533 mmol) inN, N-dimethylformamide (2 mL) to[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.0398 g,0.0533 mmol) and cuprous iodide (0.207 g, 1.07 mmol) under N₂. Themixture is stirred at 100° C. for 2 hours. The mixture is adjusted topH=6-7 with 1 N HCl and extracted with EtOAc (20 mL×3). The aqueousphase is diluted with 10% EDTA solution (30 mL), and stirred at 20° C.for 1.5 h, filtered and extracted with EtOAc (30 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over anhydroussodium sulfate and concentrated to afford title compound (112 mg, 66.4%)as a brown solid, LCMS (m/z): 317.1 [M+H]⁺.

4. Synthesis of1-[6-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-pyridyl]cyclopropanecarboxylicAcid

Add1-[6-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-pyridyl]cyclopropanecarbonitrile (112 mg, 0.354 mmol) in ethanol (3.00 mL) and water (1.00mL) to sodium hydroxide (32.0 mass %) in H₂O (3 mL). The reactionmixture is stirred at 100° C. for 12 hours. The mixture is adjusted topH=6-7 with 1 N HCl and concentrated to afford the crude. It is purifiedby prep-HPLC [Column: YMC-Actus Triart C18 150*30, 5 μm; Condition:36-66% B (A=0.05% HCl, B=acetonitrile); FlowRate: 25 mL/min] to affordthe title compound (70.0 mg, 50.0%) as a white solid, LCMS (m/z): 336.0[M+H]⁺.

5. Synthesis of1-[6-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-pyridyl]cyclopropanecarboxylicacid; Dihydrochloride

Add1-[6-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]-3-pyridyl]cyclopropanecarboxylicacid (70.0 mg, 0.177 mmol), 2-chloro-6-isopropyl-pyrazine (0.031 g,0.195 mmol) and cesium carbonate (0.173 g, 0.531 mmol) in 1, 4-dioxane(4 mL) to tris(dibenzylideneacetone)dipalladium (0.0167 g, 0.0177 mmol)and 4, 5-bis(diphenylphosphino)-9, 9-dimethylxanthene (0.0158 g, 0.0265mmol) under N₂. The mixture is stirred at 100° C. for 5 hours. The solidis filtered off. The mixture is acidified to pH=5-6, filtered andevaporated to afford the crude. It is purified by prep-HPLC [Column:YMC-Actus Triart C18 150×30, 5 μm; Condition: 36-66% B (A=0.05% HCl,B=acetonitrile); FlowRate: 25 mL/min] to afford the title compound (14.8mg, 15.2%) as a white solid, LCMS (m/z): 456.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=9.93 (br s, 1H), 9.15 (s, 1H), 8.73 (d,J=8.4 Hz, 1H), 8.69 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.91-7.84 (m, 2H), 3.75 (s, 3H),2.71-2.63 (m, 1H), 1.54-1.50 (m, 2H), 1.28-1.25 (m, 2H), 0.89 (d, J=6.8Hz, 5H).

EXAMPLE 25 Ammonium1-[4-[4-[5-[(6-cyclopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate 1.Synthesis of1-[4-[4-[5-[(6-chloropyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicAcid

Add sodium hydride in paraffin oil (0.273 g, 6.84 mmol) to a solution ofmethyl 1-(500 mg, 1.37 mmol) (prepared according to Example 17A) in DMF(5 mL) at 10° C. The reaction is stirred at 50° C. for 20 min and then2,6-dichloropyrazine (0.247 g, 1.64 mmol) is added. The reaction isstirred at 50° C. for 3 hours. The mixture is added into aq. NH₄Cl (20mL). The mixture is extracted with EtOAc (20 mL×3). Then the aqueousphase is acidified by 1 M HCl to pH=4-5. The mixture is extracted withCH₂Cl₂ (20 mL×3). The combined organic layers are washed with brine (30mL), dried over anhydrous sodium sulfate and concentrated to afford (490mg, 80.4%) as a yellow solid, LCMS (m/z): 446.1 [M+H]⁺.

2. Synthesis of Ammonia;1-[4-[4-[5-[(6-cyclopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicAcid

Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0230g, 0.0314 mmol) to a mixture of1-[4-[4-[5-[(6-chloropyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicacid (200 mg, 0.314 mmol, 70 mass %), cyclopropylboronic acid (0.0327 g,0.377 mmol) and cesium carbonate (0.205 g, 0.628 mmol) in water (0.5 mL)and 1,4-dioxane (5 mL) under nitrogen. The reaction is heated to 90° C.for 3 hours. The mixture is diluted with water (20 mL) and adjustedpH=5-6 with 1 M HCl, extracted with EtOAc (30 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over anhydroussodium sulfate and concentrated. The crude product is purified byprep-HPLC [Column: YMC-Actus Triart C18 150×30, 5 μm; Condition: 36-66%B (A=0.05% ammonia, B=acetonitrile); FlowRate: 25 mL/min] to affordtitle compound (18.5 mg, 12.3%) as a white solid. LCMS (m/z): 452.2[M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=7.89 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H),7.59-7.53 (m, 2H), 7.52-7.45 (m, 4H), 7.29 (d, J=8.0 Hz, 2H), 6.08 (brs, 4H), 3.60 (s, 1H), 1.95-1.90 (m, 1H), 1.28-1.26 (m, 2H), 0.88-0.85(m, 2H), 0.83-0.80 (m, 2H), 0.63-0.60 (m, 2H).

EXAMPLE 26A Methyl1-[4-[4-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate 1.Synthesis of methyl1-[4-[4-[5-[(6-chloropyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate

Add sodium hydride (0.0709 g, 1.77 mmol, 60 mass %) to a solution ofmethyl1-[4-[4-(5-amino-1-methyl-pyrazol-4-yl)phenyl]phenyl]cyclopropanecarboxylate(540 mg, 1.48 mmol) (prepared according to Example 17A) in DMF (10 mL)at 0° C. The reaction is stirred at 0° C. for 10 min and then2,6-dichloropyrazine (0.267 g, 1.77 mmol) is added. The reaction isheated to 30° C. for 6 hours. The mixture is diluted with water (20 mL)and extracted with EtOAc (30 mL×3). Dried over anhydrous sodium sulfate,filtered and concentrated to give the residue and purified by flashchromatography eluting with petroleum ether:EtOAc (1:1) to afford thetitle compound (160 mg, 90 mass %) as a yellow solid.

LCMS (m/z): 460.1 [M+H]⁺.

2. Synthesis of methyl1-[4-[4-[5-[(6-isopropenylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate

Add Pd(dppf)Cl₂ (0.0487 g, 0.0665 mmol) and Cs₂CO₃ (0.651 g, 2.00 mmol)methyl1-[4-[4-[5-[(6-chloropyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate(340 mg, 0.665 mmol, 90 mass %) and2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.169 g, 0.998mmol) in water (0.5 mL) and 1,4-dioxane (5 mL) under nitrogen. Thereaction is heated to 90° C. for 5 hours. The mixture is diluted withwater (20 mL) and extracted with EtOAc (30 mL×3). The combined organiclayers are washed with brine (30 mL), dried over anhydrous sodiumsulfate and concentrated. The residue is purified by flashchromatography eluting with petroleum ether:EtOAc (1:1) to afford titlecompound (325 mg, 72.6%) as a yellow solid. LCMS (m/z): 466.2 [M+H]⁺.

3. Synthesis of methyl1-[4-[4-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate

Add methyl1-[4-[4-[5-[(6-isopropenylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate(315 mg, 0.677 mmol, 90 mass %) in MeOH (10 mL) to Pd/C (20.0 mg, 10mass %) and the mixture is stirred under hydrogen (15 psi) for 18 hours.The solid is filtered off and the filtrate is evaporated to afford thetitle compound (297 mg, 93.9%) as a yellow solid. LCMS (m/z): 468.1[M+H]⁺.

EXAMPLE 26B1-[4-[4-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicAcid

Add methyl1-[4-[4-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate(295 mg, 0.635 mmol) in THF (5 mL) and water (0.5 mL) to lithiumhydroxide hydrate (0.0808 g, 1.91 mmol), the mixture is stirred at 50°C. for 18 hours. Then the mixture's pH is adjusted to 5-6 with 1.0M HClsolution and the mixture is extracted with EtOAc (30 mL×3). The combinedorganic layers are washed with brine (30 mL), dried over anhydroussodium sulfate and concentrated. The crude product is purified byprep-HPLC (column: Phenomenex Gemini 150×25 mm×10 μm, Gradient: 50-80% B(A=water/0.05% HCl, B=acetonitrile), Flow rate: 25 mL/min). The desiredfractions are lyophilized to afford the title compound (112.6 mg, 38.3%)as a yellow solid. LCMS (m/z): 454.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=9.19 (s, 1H), 7.91-7.83 (m, 3H), 7.61-7.51(m, 6H), 7.36 (d, J=8.4 Hz, 2H), 3.65 (s, 3H), 2.84-2.74 (m, 1H),1.48-1.43 (m, 2H), 1.17-1.13 (m, 2H), 1.07 (d, J=6.8 Hz, 6H).

EXAMPLE 271-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid 1. Synthesis of1-[4-[6-[5-[(6-chloropyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid

Add sodium hydride (0.293 g, 7.32 mmol, 60% in paraffin oil) to thesolution of1-[4-[6-(5-amino-1-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylicacid (0.600 g, 1.46 mmol, 85 mass %) (prepared according to Example 1A)in DMF (2 mL) at 20° C. The reaction is stirred at 50° C. for 20 minutesand then 2, 6-dichloropyrazine (0.264 g, 1.76 mmol) is added. Thereaction is stirred at 50° C. for 3 hours. The mixture is added intowater (20 mL). The mixture is extracted with EtOAc (20 mL×3). Then theaqueous phase is acidified by 1 M HCl to pH=4-5. The mixture isextracted with EtOAc (20 mL×3). The combined organic layers are washedwith brine (30 mL), dried over anhydrous sodium sulfate andconcentrated, to afford title compound (495 mg, 75%) as a yellow solid.LCMS (m/z): 447.0 [M+H]⁺.

2. Synthesis of1-[4-[6-[5-[(6-isopropenylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid

Add Pd(dppf)Cl₂ (0.081 g, 0.111 mmol) to the suspensions of2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.282 g, 1.66mmol),1-[4-[6-[5-[(6-chloropyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid (495 mg, 1.11 mmol) and sodium carbonate (352 mg, 3.32 mmol) inwater (0.5 mL) and 1,4-dioxane (5 mL) under nitrogen. The reaction isheated to 90° C. for 3 hours. The mixture is diluted with water (20 mL)and adjusted pH=5-6 with 1 M HCl, extracted with EtOAc (30 mL×3). Thecombined organic layers are washed with brine (30 mL), dried overanhydrous sodium sulfate and concentrated. The residue is purified byflash chromatography on silica gel eluting with petroleum ether:EtOAc(2:1) to afford compound (293 mg, 58%) as a yellow solid. LCMS (m/z):453.0 [M+H]⁺.

3. Synthesis of1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicAcid

Add1-[4-[6-[5-[(6-isopropenylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid (400 mg, 0.575 mmol, 65 mass %) in methanol (10 mL) to palladium onactivated carbon (120 mg, 10 mass %) at room temp. the mixture isstirred under molecular hydrogen (15 psi) at 10° C. for 18 hours. Thesolid is filtered off and the filtrate is evaporated to afford thecrude. The crude product is purified by prep-HPLC [Column: YMC-ActusTriart C18 150*30, 5 μm; Condition: 36-66% B (A=0.05% HCl,B=acetonitrile); flow rate: 25 mL/min] to afford title compound (31.1mg, 11%) as a white solid. LCMS (m/z): 455.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ=9.98 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.50(d, J=8.0 Hz, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.89-7.83(m, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 3.78 (s, 3H),2.75-2.66 (m, 1H), 1.53-1.46 (m, 2H), 1.21-1.16 (m, 2H), 0.97-0.86 (m,6H).

LPAR1 Calcium Flux Assays

A cDNA encoding the human LPAR1 receptor is synthesized and cloned intopDNA3 expression plasmid. The plasmid is transfected in U937 cells usingLipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressinghuman LPAR1 are selected using puromycin and identified as cells thatshow Ca-influx in response to LPA.

U937 cells overexpressing human LPAR1 are seeded at 100,000 cells perwell in a 96-well fibronectin (10 ug/ml) coated plate in 60 μl of assaybuffer (HBSS containing 20 mM HEPES and 0.2% BSA) and then incubated for60 minutes. Then 50 μl of a calcium indicator dye (Fluo-4 NW, MolecularProbes) are added to each well and incubation continued for 30 minutesat 37° C. and then 30 minutes at room temperature. 50 μl of testcompounds in 4% DMSO are added to the cells and incubation continued atroom temperature for 40 minutes. Cells are the stimulated by theaddition of 50 μl of 128 nM LPA and intracellular calcium is measuredusing the FLIPR TETRA (Molecular Devices). IC50 values are determinedusing “Genedata Screener” analysis tool.

LPAR3 Calcium Flux Assays

A cDNA encoding the human LPAR3 receptor is synthesized and cloned intopDNA3 expression plasmid. The plasmid is transfected in U2OS cells usingLipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressinghuman LPAR3 are selected using neomycin and identified as cells thatshow Ca-influx in response to LPA.

U2OS cells overexpressing human LPAR3 are seeded at 20,000-40,000 cellsper well in a 96-well poly-D-lysine coated plate one day before theassay. Prior to the assay, the cells are washed once with assay buffer(HBSS containing 20 mM HEPES and 0.2% BSA) and then incubated in 50 μlof assay buffer for 60 minutes. Then 50 μl of a calcium indicator dye(Fluo-4 NW, Molecular Probes) are added to each well and incubation iscontinued for 30 minutes at 37° C. and then 30 minutes at roomtemperature. 50 μl of test compounds in 4% DMSO are added to the cellsand incubation continued at room temperature for 40 minutes. Cells arestimulated by the addition of 50 μl of 128 nM LPA and intracellularcalcium is measured using the FLIPR TETRA (Molecular Devices). IC50values are determined using “Genedata Screener” analysis tool.

LPAR1 Membrane Binding Assay

The ability of a compound to inhibit binding of a ligand(1-(4′-(4-(((benzyloxy)carbonyl)amino)-3-methylisoxazol-5-yl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylicacid) to LPAR1 is assessed via a membrane binding assay. Membranecontaining LPAR1 was purchased from Cerep (Cat. No. 290312RB). Prior tothe assay, membrane is thawed and homogenized for 15 seconds. 50 μl oftest compounds and 50 μl of radio labeled ligand are added to the96-well plates and then 50 of μl membrane (50-400 ug/ml) are added.Next, 50 μl of SPA PVT WGA beads are added (1-5 mg/ml) and the platesare sealed and incubated at room temperate for 5 minutes. Radio activityis measured by Beta Counter and IC50 values are determined using“Genedata Screener” analysis tool.

Calcium Influx of Human Hepatic Stellate Cells (LX-2)

Human hepatic stellate cell line LX-2 is purchased from EMD Millpore.LX-2 cells are seeded at 20,000-40,000 cells per well in a 96-wellpoly-D-lysine coated plate one day before the assay. Prior to the assay,the cells are washed once with assay buffer (HBSS containing 20 mM HEPESand 0.2% BSA) and then incubated in 50 μl of assay buffer for 60minutes. Then 50 μl of a calcium indicator dye (Fluo-4 NW, MolecularProbes) are added to each well and incubation is continued for 30minutes at 37° C. and then 30 minutes at room temperature. 50 μl of testcompounds in 4% DMSO are added to the cells and incubation is continuedat room temperature for 40 minutes. Cells are stimulated by the additionof 50 μl of 128 nM LPA and intracellular calcium is measured using theFLIPR TETRA (Molecular Devices). IC50 values are determined using“Genedata Screener” analysis tool.

LPAR1 Cytokine Release Assay

Human MG63 cells are seeded at 20,000 per well in 96-well plates andincubated in MEM medium. One day later, the cell culture medium isremoved and 60 μl of test compounds are added to each well. 30 minuteslater, 60 μl of LPA (10 μM) are added to each well. 24 hours later, 50μl of supernatant from each well are taken and IL-6 levels are measureby using ELISA kit (R&D Systems, Cat. No. D6050). IC50 values aredetermined using “Genedata Screener” analysis tool.

Representative active compounds of the present invention (“B” Examples,as opposed to ester prodrugs, “A” Examples) were assayed essentially asdescribed above and the results were summarized in Table 1 below:

TABLE 1 LPAR1 Cytokine LPAR1 LPAR3 LPAR1 Release Example IC50 IC50Binding LX-2 Assay No. (nM) (nM) ki (nM) (nM) IC50 (nM)  1 74.4 1330 nt*37.2 nt  2 17.2 327 nt 9.22 nt  3 8.61 2480 44.2 3.8 nt  4 16.7 159080.5 8.67 nt  5 26.9 49.6 51.4 17.1 nt  6 122 5270 115 60.5 nt  7 27.11050 72.3 16.3 nt  8 22 >10000 nt 7.13 nt  9 17.9 >10000 nt 10.5 nt 109.86 4420 12.5 5.41 nt 11 11.1 495 34.6 10 nt 12 24.4 4280 40.9 14.4 nt13 44 804 28 10.5 nt 14 45.8 >10000 nt 13.2 nt 15 42.9 >10000 94.8 19.4nt 16 29.3 4620 53.8 18.2 nt 17 54.7 1830 nt 23.1 5.81 18 24 2360 24.57.94 6.67 19 88.1 2400 nt 16.3 nt 20 29.3 341 12.7 12 3.95 21 36.3 161027.6 14.1 8.81 22 30.9 1170 nt 10.4 11.2 23 111 >10000 nt 21.5 183 24 482760 46.2 15.3 nt 25 52.9 >10000 30.8 24.2 nt 26 23.6 >10000 18.8 13.14.79 27 20.6 1980 15.3 8.88 nt *nt: not tested.

Rodent Pharmacokinetics

The pharmacokinetics of compounds are determined in male Sprague-Dawleyrats or C57 mice. The rats are administered a single 1 mg/kg intravenous(IV) and 10 mg/kg oral gavage (PO) dose. The vehicles are 20% Captisolw/v in 25 mM NaPO4 buffer, pH8 and 1% hydroxyethylcellulose/0.25%polysorbate 80 and 0.05% antifoam 1510-US in distilled water for theintravenous and oral dose, respectively. Blood samples are collected atpredose (PO only), 0.08 (IV only), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hafter initiation of compound administration. Blood samples arecentrifuged to obtain plasma. The plasma samples are analyzed byLC-MS/MS to determine compound concentrations.

Representative active compounds (as opposed to ester prodrugs) of thepresent invention assayed essentially as described above and the resultswere summarized in Table 2A and 2B below:

TABLE 2A Mouse PK AUC Example (hr*nM, 10 CL Vdss No. mg/kg, PO)(mL/min/kg) (L/kg) % F 21 16333 4.99 1.46 24.8 26 9065 2.00 2.00 30.0 2738385 3.50 0.953 40.8

TABLE 2B Rat PK AUC Example (hr*nM, 10 CL Vdss No. mg/kg, PO)(mL/min/kg) (L/kg) % F 20 70872 2.94 0.721 57.5 27 80123 4.23 0.799 93.6

Diet-Induced Liver Inflammation and Fibrosis

Male C57B1/6 mice (7-8 weeks old) are given free access to food andwater. Mice are fed with high fat, high sucrose and high cholesterolfood for 196 days. Then animals will be administrated orally withvehicle or test compounds once daily for 77 days at a volume of 5 ml/kg.Body weight and food intake will be measured twice a week, after twoweeks, BW and FI will be measured once a week. At the end of study,animals will be euthanized by CO2 suffocation. Liver samples of theanimals are collected and fixed in 10% NBF. Liver samples are preparedafter 20 to 24 hours of fixation in 10% NBF and prepared into FFPEblocks. Slide sections of FFPE blocks are processed with H&E andMasson's Trichrome staining. Histopathology interpretation and resultswill be provided by qualified pathologists. The data are plotted usingGraphpad prism and statistical differences between groups determined.

Active compound Example no. 27 (as opposed to ester prodrug) was assayedessentially as described above and the results were summarized in Table3 below:

TABLE 3 Example No. 27 Example No. 27 vehicle (10 mg/kg) (30 mg/kg)Inflammation 2.7 2.1* 2.3^(# ) Score Peri-sinusoidal 1.37 1.30 1.07^($)Fibrosis Score *P<0001 ^(#)P<0.003 ^($)P<0.014

Mouse Intravenous LPA-Induced Histamine and Eicosanoids Release

A mouse intravenous LPA-induced histamine and eicosanoids release modelis utilized to determine the in vivo potency of the compounds of thepresent invention. Male C57BL/6J mice weighing 20-25 grams are givenfree access to standard mouse chow and water. LPA is dissolved in 0.1%fatty acid-free bovine serum albumin to generate solution at 2 mg/mL.Test compounds are formulated in 0.5% methyl cellulose plus 0.25% Tween80 to generate required concentrations one day before the experiment andstored in a refrigerator until use. Animals are dosed orally with testcompounds at 10 ml/kg 2 hours before the intravenous LPA dosing (300 ugper mouse) with 30 gauge needles through tail vain. Two hours after LPAdosing the animals are euthanized by CO2 suffocate. Blood will becollected by cardiac puncture. Blood samples are kept on ice for morethan 5 minutes and centrifuged at 4000 rpm for 10 minutes at 4° C. togenerate supernatant plasma. The plasma histamine, methylimidazol aceticacid and eicosanoids levels are measured by LC/MS.

Active compound Example Nos. 20 and 27 (as opposed to ester prodrug)were assayed essentially as described above and the results weresummarized in Table 4 below:

TABLE 4 Example No. Example No. 20 (10 mg/kg) 27 (10 mg/kg) Releasedfactors % of inhibition % of inhibition histamine NA*  89.5 ± 1.6methylimidazoleacetic 103.5 ± 0.6 100.8 ± 3.4 acid 12-  68.8 ± 6.0 NAhydroxyeicosatetraenoic acid 9,10-cis epoxide of  83.4 ± 6.4 NA linoleicacid *not available.

1. A compound of the formula

wherein, X¹ and X² are each independently CH or N, and X³ is C—R² or N,provided that when X¹ is CH, then X² is CH and X³ is C—R², and providedthat when X¹ is N, then no more than one of X² and X³ may be N; Y¹ andY² are CH or N, provided that only one of Y¹ or Y² may be N; R¹ isisopropyl, isobutyl, t-butyl, 2-hydroxyprop-2-yl, cyclopropyl,cyclopropyloxy, t-butyloxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy,2-fluoroprop-2-yl, 1,1-difluoroethyl, trifluoromethyl, isopropyloxy, or2-methoxyprop-2-yl; R² is H or fluoro; R³ is H, halogen, C₁-C₃ alkyl,C₁-C₃ alkoxy, C₁-C₃ alkoxymethyl, CF₃, cyanomethyl or cyano; R⁴ is H,halogen, C₁-C₃ alkyl, CF₃ or cyano; R⁵ is H, methyl, ethyl, propyl,isopropyl, or cyclopropyl; or a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1, wherein X¹ is N, or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1, wherein X¹ is CH, or a pharmaceutically acceptable saltthereof.
 4. The compound according to claim 1, wherein Y¹ is CH, or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 1, wherein R¹ is isopropyl, or a pharmaceutically acceptable saltthereof.
 6. The compound according to claim 1, wherein R¹ iscyclopropyloxy, or a pharmaceutically acceptable salt thereof.
 7. Thecompound according to claim 1, wherein R⁵ is hydrogen, or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 1, which is:1-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[[6-(cyclobutoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[5-fluoro-6-[5-[[6-(1-fluoro-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[[6-(3,3-difluorocyclobutoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[[6-(1-methoxy-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-methyl-phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylicacid,1-[2-cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[5-fluoro-6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[[6-(1,1-difluoroethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[[6-(1-fluoro-1-methyl-ethyl)pyrazin-2-yl]amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-(methoxymethyl)phenyl]cyclopropanecarboxylicacid,1-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[4-[5-[(6-isobutylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicacid,1-[4-[2-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrimidin-5-yl]phenyl]cyclopropanecarboxylicacid,1-[4-[5-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]pyrazin-2-yl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[1-methyl-5-[[6-(trifluoromethyl)pyrazin-2-yl]amino]pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid,1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-methyl-phenyl]cyclopropanecarboxylicacid, Ammonia;1-[5-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-2-pyridyl]cyclopropanecarboxylicacid,1-[6-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]-3-pyridyl]cyclopropanecarboxylicacid, Ammonium1-[4-[4-[5-[(6-cyclopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylate,1-[4-[4-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicacid, or1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid; or a pharmaceutically acceptable salt thereof.
 9. The compound ofclaim 1 which is,1-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylicacid, or a pharmaceutically acceptable salt thereof.
 10. The compound ofclaim 1 which is,1-[4-[4-[5-[(6-isopropylpyrazin-2-yl)amino]-1-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylicacid, or a pharmaceutically acceptable salt thereof.
 11. Apharmaceutical composition, comprising a compound according to claim 1,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier, diluent, or excipient.
 12. A methodfor treating nonalcoholic steatohepatitis (NASH), comprisingadministering to a mammal in need thereof, an effective amount of acompound of the formula

wherein, X¹ and X² are each independently CH or N, and X³ is C—R² or N,provided that when X¹ is CH, then X² is CH and X³ is C—R², and providedthat when X¹ is N, then no more than one of X² and X³ may be N; Y¹ andY² are CH or N, provided that only one of Y¹ or Y² may be N; R¹ isisopropyl, isobutyl, t-butyl, 2-hydroxyprop-2-yl, cyclopropyl,cyclopropyloxy, t-butyloxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy,2-fluoroprop-2-yl, 1,1-difluoroethyl, trifluoromethyl, isopropyloxy, or2-methoxyprop-2-yl; R² is H or fluoro; R³ is H, halogen, C₁-C₃ alkyl,C₁-C₃ alkoxy, C₁-C₃ alkoxymethyl, CF₃, cyanomethyl or cyano; R⁴ is H,halogen, C₁-C₃ alkyl, CF₃ or cyano; R⁵ is H, methyl, ethyl, propyl,isopropyl, or cyclopropyl; or a pharmaceutically acceptable saltthereof.
 13. A method for treating fibrosis, comprising administering toa mammal in need thereof, an effective amount of a compound of theformula

wherein, X¹ and X² are each independently CH or N, and X³ is C—R² or N,provided that when X¹ is CH, then X² is CH and X³ is C—R², and providedthat when X¹ is N, then no more than one of X² and X³ may be N; Y¹ andY² are CH or N, provided that only one of Y¹ or Y² may be N; R¹ isisopropyl, isobutyl, t-butyl, 2-hydroxyprop-2-yl, cyclopropyl,cyclopropyloxy, t-butyloxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy,2-fluoroprop-2-yl, 1,1-difluoroethyl, trifluoromethyl, isopropyloxy, or2-methoxyprop-2-yl; R² is H or fluoro; R³ is H, halogen, C₁-C₃ alkyl,C₁-C₃ alkoxy, C₁-C₃ alkoxymethyl, CF₃, cyanomethyl or cyano; R⁴ is H,halogen, C₁-C₃ alkyl, CF₃ or cyano; R⁵ is H, methyl, ethyl, propyl,isopropyl, or cyclopropyl; or a pharmaceutically acceptable saltthereof.
 14. The method according to claim 12, wherein the mammal is ahuman.
 15. (canceled)
 16. (canceled)
 17. (canceled)
 18. A method fortreating inflammatory diseases, comprising administering to a mammal inneed thereof, an effective amount of a compound of the formula

wherein, X¹ and X² are each independently CH or N, and X³ is C—R² or N,provided that when X¹ is CH, then X² is CH and X³ is C—R², and providedthat when X¹ is N, then no more than one of X² and X³ may be N; Y¹ andY² are CH or N, provided that only one of Y¹ or Y² may be N; R¹ isisopropyl, isobutyl, t-butyl, 2-hydroxyprop-2-yl, cyclopropyl,cyclopropyloxy, t-butyloxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy,2-fluoroprop-2-yl, 1,1-difluoroethyl, trifluoromethyl, isopropyloxy, or2-methoxyprop-2-yl; R² is H or fluoro; R³ is H, halogen, C₁-C₃ alkyl,C₁-C₃ alkoxy, C₁-C₃ alkoxymethyl, CF₃, cyanomethyl or cyano; R⁴ is H,halogen, C₁-C₃ alkyl, CF₃ or cyano; R⁵ is H, methyl, ethyl, propyl,isopropyl, or cyclopropyl; or a pharmaceutically acceptable saltthereof.